Abstract
Background
Human papillomavirus (HPV) vaccination has the potential to enhance prevention of cervical cancer, especially in countries where screening programmes are currently unaffordable or impractical. Rare adverse events and longer‐term benefits of HPV vaccination, such as effects on cancer rates, are difficult to examine in randomised controlled trials (RCTs) and require large data from population‐level studies to inform decision‐making.
Objectives
We aimed to assess population‐level effects of HPV vaccination programmes on HPV‐related disease and harms from vaccination.
Search methods
We conducted electronic searches on 11 September 2024 in CENTRAL (Cochrane Library), Ovid MEDLINE and Ovid Embase. We also searched vaccine manufacturer websites and checked reference lists from an index of HPV studies and other relevant systematic reviews.
Selection criteria
We included studies that assessed the impact of HPV vaccination on the general population. This included population‐level studies comparing outcomes before and after the introduction of HPV vaccine. We also included individual‐level, non‐randomised comparative studies, such as cohort studies, case‐control studies, cross‐sectional studies and self‐controlled case series.
Data collection and analysis
We used methods recommended by Cochrane. Two review authors carried out data extraction independently using pretested data extraction forms. We assessed the risk of bias of all included effect estimates using different tools according to study design. We carried out quantitative and qualitative data synthesis separately by outcome and study design. We performed meta‐analysis on studies that reported effect estimates adjusted for confounding, with a focus on those receiving HPV vaccination at or before the age of 16 years (the target age group for vaccination). We rated the certainty of the evidence with GRADE.
Main results
We included 225 studies from 347 records in this review, evaluating over 132 million people. We included 86 cohort studies, four case‐control studies, 46 cross‐sectional studies, 69 pre‐post vaccine introduction studies, five RCT extensions and two self‐controlled case series. Thirteen additional studies reported on more than one type of analysis. Of the included studies, 177 reported only on females, 11 only males and 37 a combination of males and females. Risk of bias ranged from overall moderate risk to critical risk.
Clinical outcomes
There was moderate‐certainty evidence from 20 studies that HPV vaccination reduces the incidence of cervical cancer. Five cohort studies including 4,390,243 females reported adjusted estimates showing a reduced risk of cervical cancer following HPV vaccination in the long term (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.25 to 0.56; I2 = 88%). There was a significant interaction with age at vaccination, with a greater risk reduction in younger people. For those vaccinated at or before 16 years of age, covering 4.54 million person‐years, there was an 80% reduced risk of cervical cancer (RR 0.20, 95% CI 0.09 to 0.44; I2 = 69%). One cohort study, one case‐control study, one cross‐sectional study and three RCT extension studies all reported no cases of cervical cancer in the HPV vaccine groups. Eight pre‐post vaccine introduction studies each reported a reduction in cervical cancer incidence following HPV vaccine introduction but did not provide data in a form that allowed for meta‐analysis.
There was moderate‐certainty evidence from 23 studies that HPV vaccination reduces the incidence of cervical intraepithelial neoplasia grade 3 or higher (CIN3+), including 12 cohort studies. For 1.5 million females vaccinated at or before the age of 16 years in two cohort studies, there was a reduction of CIN3+ incidence of 74% in the long term (RR 0.26, 95% CI 0.12 to 0.56; I2 = 80%). Three case‐control studies, one RCT extension study and three cross‐sectional studies also reported a decreased risk of CIN3+ in vaccinated participants. One cross‐sectional study reported no difference in the risk of CIN3+. Three pre‐post vaccine introduction studies reported a decrease in CIN3+ incidence following HPV vaccine introduction.
There was moderate‐certainty evidence from 37 studies that HPV vaccination reduces the incidence of CIN2+. In cohort studies with females vaccinated at or before the age of 16 years, a reduction in risk was seen in the medium term (RR 0.59, 95% CI 0.54 to 0.65; 2 cohort studies, 233,468 females; I2 = 0%) and long term (RR 0.38, 95% CI 0.31 to 0.45; 5 cohort studies, 6,455,176 females; I2 = 64%).
There was moderate‐certainty evidence from 47 studies that HPV vaccination reduces the incidence of anogenital warts. From the cohort studies with adjusted estimates, the pooled impact of HPV vaccination on rates of anogenital warts indicated a reduction of 47% in the medium term (RR 0.53, 95% CI 0.37 to 0.77; 4 studies, 6,430,295 females and 313 males; I2 = 98%) and 53% in the long term (RR 0.47, 95% CI 0.36 to 0.61; 13 studies, 4.5 million person‐years plus 5,802,969 females and males; I2 = 99%). Twenty‐three pre‐post vaccine introduction studies reported a decrease in anogenital warts incidence following the introduction of HPV vaccine. Six studies reported no difference in anogenital warts incidence.
There was only very low‐certainty evidence on the effect of HPV vaccination on the incidence of adenocarcinoma in situ (three studies) and vulval cancer (five studies). No studies were identified that reported on community rates of serious adverse events following HPV vaccination.
Specific adverse events
Across a range of study designs, HPV vaccination was not associated with an increased risk of postural orthostatic tachycardia syndrome, chronic fatigue syndrome/myalgic encephalomyelitis, paralysis, complex regional pain syndrome, premature ovarian failure, infertility or sexual activity (all moderate‐certainty evidence). There was evidence that suggests HPV vaccination was not associated with an increased risk of Guillain‐Barré syndrome (low‐certainty evidence).
Authors' conclusions
There are now long‐term outcome data from different countries and from different study designs that consistently report a reduction in the development of high‐grade CIN and cervical cancer in females vaccinated against HPV in early adolescence. Data show that there is greater benefit to vaccinating younger adolescents prior to becoming sexually active. There is evidence that HPV vaccination does not increase the risk of the most common adverse events reported on social media.
Plain language summary
What are the benefits and risks of different human papillomavirus (HPV) vaccines for preventing cervical cancer and other HPV‐related disease?
Key messages
HPV vaccination:
‐ reduces the incidence of cervical cancer by around 80% in people vaccinated at or before the age of 16 years;
‐ reduces the incidence of high‐grade cervical pre‐cancer lesions, as well as anogenital warts;
‐ is not associated with an increased risk of long‐term side effects or infertility;
‐ is more effective when given at or before the age of 16 years, before onset of sexual activity.
What is HPV?
Human papillomavirus (HPV) is transmitted between people through sexual contact, including vaginal, anal or oral sex. There are many types of HPV. Some types are harmless, but other types can cause cancer. Cervical cancer is the most common type of cancer that HPV can cause, but it can also cause vaginal, vulval, penile, anal, and head and neck cancer, as well as anogenital warts (a sexually transmitted infection caused by certain types of human papillomavirus). From the time of HPV infection, cervical cancer usually takes more than 10 years to develop, and other cancers take longer.
How can HPV vaccines be beneficial?
In girls and boys, HPV vaccines aim to prevent HPV infection, which can sometimes cause cancer and anogenital warts. The HPV vaccines do not work well in people that have already been exposed to HPV. For this reason, most vaccination programmes aim to offer the vaccine to young people before they become sexually active.
What did we want to find out?
We wanted more information on questions about long‐term and rare outcomes that cannot be answered by randomised controlled trials (studies where people are assigned randomly to two or more treatment groups):
‐ What are the effects of introducing HPV vaccination on community rates of cervical, vaginal, vulval, anal and penile cancer, and the pre‐cancerous stages of disease during the development of cancer?
‐ What are the effects of introducing HPV vaccination on the number of people who develop anogenital warts and the number of people who undergo treatment for HPV‐related disease?
We also wanted to know if HPV vaccines were associated with any harmful effects, especially those discussed most frequently on social media.
What did we do?
We searched for studies that evaluated the impact of HPV vaccination on population levels of cervical and other cancers, high‐grade pre‐cancer lesions (abnormal cell changes that occur after a persistent high‐risk HPV infection and can develop into cancer if untreated), anogenital warts, treatment rates, HPV infections and unwanted or harmful (adverse) events. These included studies following groups of people after receiving HPV vaccination and studies observing the change in these diseases after national‐level introduction of HPV vaccination.
We also searched social media sites (WebMD and X (formerly Twitter)) for commonly mentioned adverse events related to HPV vaccination. We searched for and included studies evaluating the impact of HPV vaccination on these events.
What did we find?
We found 225 suitable studies from around the world that reported on the benefits and harms of HPV vaccination, including over 132 million people.
HPV vaccination probably reduces the incidence of cervical cancer by around 80% in people vaccinated at or before the age of 16 years. The reduction is lower for people vaccinated later.
HPV vaccination probably reduces the incidence of high‐grade cervical pre‐cancer lesions (CIN3+, CIN3, CIN2+ and CIN2), as well as anogenital warts. Again, reductions are greater in people who received the HPV vaccine at or before the age of 16 years.
There was lower‐certainty evidence for the effect of HPV vaccination on rare diseases that take much longer to develop, such as adenocarcinoma in situ, other pre‐cancer lesions and other cancers related to HPV (e.g. vaginal, vulval, anal and penile cancer). We identified fewer studies on these outcomes.
For most of the specific adverse events we looked at, including postural orthostatic tachycardia syndrome, chronic fatigue syndrome/myalgic encephalomyelitis, paralysis, complex regional pain syndrome, Guillain‐Barré syndrome and infertility, there was moderate‐certainty evidence that HPV vaccination likely does not increase the risk of developing them. HPV vaccination also did not increase sexual activity.
HPV vaccination also appears to reduce treatment rates associated with HPV disease, increases attendance at cervical screening programmes and reduces HPV infections.
What are the limitations of the evidence?
We are moderately confident in our results for cervical cancer, high‐grade cervical disease, anogenital warts and specific harms. However, better and larger studies could show more reliable and precise results about the amount of protection.
How up‐to‐date is this evidence?
The evidence is up‐to‐date to September 2024.
Summary of findings
Summary of findings 1. Summary of findings – clinical outcomes.
|
Population: general population of any age Setting: any setting Intervention: full or partial series HPV vaccination Comparator: no vaccination | ||||
| Outcome | Number of studies (participants) | Summary of effect | Overall certainty of the evidence | Interpretation of findings |
| Invasive cervical cancer | Six cohort studies (4,419,387 females plus 27,946 cases of cervical cancer) One case‐control study (12,296 females) Three RCT extension studies (47,456 females) One cross‐sectional study (1392 females) Nine pre‐post vaccine introduction studies (> 1,030,882 cases of cervical cancer) |
Of the six cohort studies, five reported a reduced risk of cervical cancer following HPV vaccination (RR 0.37, 95% CI 0.25 to 0.56). One cohort study did not report any cases of cervical cancer in the HPV vaccine group. The case‐control study, cross‐sectional study and the three RCT extension studies all reported no cases of cervical cancer in the HPV vaccine groups. All nine pre‐post vaccine introduction studies reported a reduction in cervical cancer incidence between the pre‐ and post‐introduction periods. |
MODERATEa
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination probably reduces the incidence of cervical cancer. |
| Adenocarcinoma in situ (AIS) | One cross‐sectional study (1392 females) Two pre‐post vaccine introduction studies (> 5475 cases of AIS) |
The cross‐sectional study reported no cases of AIS in the HPV vaccine group. One pre‐post vaccine introduction study reported an increase in AIS incidence between the pre‐ and post‐introduction period, while the other reported a reduction. |
VERY LOWb,c,d
⊕◯◯◯ Downgraded due to serious methodological limitations, inconsistency and imprecision |
We are unclear about the effect of HPV vaccination on AIS incidence because the certainty of the evidence is very low. |
| Cervical intraepithelial neoplasia grade 3 or higher (CIN3+) | Twelve cohort studies (3,105,713 females) Three case‐control studies (26,595 females) One RCT extension study (3148 females) Five cross‐sectional studies (219,953 females) Three pre‐post vaccine introduction studies (116,139 females) |
Of the 12 cohort studies, one did not report any cases of CIN3+. One study reported a reduction in the medium term (RR 0.43, 95% CI 0.35 to 0.53) and seven studies showed a reduction in the long term (RR 0.39, 95% CI 0.32 to 0.48). Three case‐control studies reported a reduced risk of CIN3+ in vaccinated participants. The RCT extension study reported a decrease in CIN3+ incidence in vaccinated participants. Four cross‐sectional studies reported a decreased risk of CIN3+ in vaccinated participants. One cross‐sectional study reported no difference in risk of CIN3+. Three pre‐post vaccine introduction studies reported a decrease in CIN3+ incidence between the pre‐ and post‐introduction periods. |
MODERATEe
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination probably reduces the incidence of CIN3+. |
| Invasive vulval cancer | One RCT extension study (189,901 person‐years) Four pre‐post vaccine introduction studies (> 36,563 cases of vulval cancer) |
The RCT extension study reported no cases of vulval cancer in vaccinated participants. Two pre‐post‐vaccine introduction studies reported a decrease in vulval cancer incidence between the pre‐ and post‐introduction periods, while one reported an increase. The other study reported inconsistent results, with some ethnic groups seeing an increased incidence and others a decrease. |
VERY LOWf,g,h
⊕◯◯◯ Downgraded due to methodological limitations and serious imprecision |
We do not know about the effect of HPV vaccination on vulval cancer incidence because the certainty of the evidence is very low. |
| Cervical intraepithelial neoplasia grade 2 or higher (CIN2+) | Fourteen cohort studies (7,059,815 females) Three case‐control studies (142,073 females) Two RCT extensions (11,675 females) Eleven cross‐sectional studies (205,994 females) Seven pre‐post vaccine introduction studies (4,914,524 females) |
Twelve cohort studies reported a reduced risk of CIN2+ following HPV vaccination (RR 0.51, 95% CI 0.37 to 0.69) and one reported no difference in risk of CIN2+ between vaccinated and unvaccinated participants. One cohort study did not report any cases of CIN2+ in the HPV vaccine group. Three case‐control studies all reported reduced odds of CIN2+ in vaccinated participants. One RCT extension study reported no cases of CIN2+ in the vaccinated participants and the other reported a decrease in CIN2+ with HPV vaccine. Three cross‐sectional studies reported a reduced risk of CIN2+ in vaccinated participants (RR 0.47, 95% CI 0.34 to 0.64). Five cross‐sectional studies reported no difference in risk between vaccinated and unvaccinated participants. Three cross‐sectional studies reported no cases of CIN2+ in the vaccinated participants. Six pre‐post vaccine introduction studies reported a reduction in CIN2+ incidence between the pre‐ and post‐introduction periods and one study reported an increased incidence. |
MODERATEi
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination probably reduces the incidence of CIN2+. |
| Anogenital warts | Fifteen cohort studies (5,226,044 person‐years plus 12,035,299 females and males) Three cross‐sectional studies (19,662 females) Thirty‐one pre‐post vaccine introduction studies (107,112,909 person‐years plus 16,116,268 females and males plus 13,026 cases of anogenital warts) |
Thirteen cohort studies reported a reduced risk of anogenital warts in vaccinated compared with unvaccinated participants (RR 0.47, 95% CI 0.36 to 0.61). Two cohort studies reported no difference in risk of anogenital warts between vaccinated and unvaccinated participants. One cross‐sectional study reported a decreased odds of anogenital warts in vaccinated compared with unvaccinated participants. One cross‐sectional study reported no difference in odds, and one did not report any cases of anogenital warts in the exposed group. Twenty‐five pre‐post vaccine introduction studies reported a decrease in anogenital warts incidence following the introduction of HPV vaccine. Six studies reported no difference in anogenital warts incidence. |
MODERATEj
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination probably reduces the incidence of anogenital warts. |
| Serious adverse events | No studies were identified that reported on this outcome. | |||
AIN: anal intraepithelial neoplasia (precancer of the perianal skin); AIS: adenocarcinoma in situ (precancer of the glandular cells of the cervix, also known as cervical intraepithelial glandular neoplasia (CGIN)); CI: confidence interval; CIN: cervical intraepithelial neoplasia (precancer of the squamous (skin‐like) cells of the cervix); CIN2: cervical intraepithelial neoplasia grade 2; CIN2+: cervical intraepithelial neoplasia grade 2 or higher; CIN3: cervical intraepithelial neoplasia grade 3; CIN3+: cervical intraepithelial neoplasia grade 3 or higher; HPV: human papillomavirus; PeIN: penile intraepithelial neoplasia (precancer of the penile skin); RCT: randomised controlled trial; RR: risk ratio; VaIN: vaginal intraepithelial neoplasia (precancer of the vaginal skin/mucosa); VIN: vulval intraepithelial neoplasia (precancer of the vulval skin)
aThree cohort studies were at moderate risk of bias, two were at serious risk and one at critical risk. The main concerns for bias were the potential for residual confounding and selective reporting. The other designs were at moderate, serious or critical risk of bias. Overall, we have downgraded one level for methodological limitations.
bAll three studies were at critical risk of bias. The main concerns for bias were the potential for residual confounding and classification of the interventions. Overall, we have downgraded two levels for serious methodological limitations.
cDowngraded one level for inconsistency – studies show no effect, a possible harm and a possible benefit of HPV vaccination.
dDowngraded one level for imprecision – one cross‐sectional study with no cases, one pre‐post vaccine introduction study with an unclear number of cases.
eEight cohort studies were at serious risk of bias and four at critical risk of bias. The other study designs were at moderate, serious or critical risk of bias. The main concerns for bias were the potential for residual confounding and selection bias. Overall, we have downgraded one level for methodological limitations.
fOne RCT extension study was at serious risk of bias, four pre‐post vaccine introduction studies were at serious risk of bias. The main concerns for bias were the potential for residual confounding and classification of the interventions. Overall, we have downgraded one level for methodological limitations.
gDowngraded one level for inconsistency – studies show no effect, a possible harm and a possible benefit of HPV vaccination.
hDowngraded one level for imprecision – one study with no cases in the exposed group, two studies with an unclear number of events counted.
iOne cohort study was at moderate risk of bias, seven cohort studies were at serious risk and six were at critical risk of bias. The other designs were at moderate, serious or critical risk of bias. Overall, we have downgraded one level for methodological limitations.
jOne cohort study was at moderate risk of bias and 13 at serious risk of bias. The main concern for bias was the potential for residual confounding. The other designs were at serious or critical risk of bias. Overall, we have downgraded one level for methodological limitations.
Summary of findings 2. Summary of findings – specific adverse events.
|
Population: general population of any age Setting: any setting Intervention: full or partial series HPV vaccination Comparator: no vaccination | ||||
| Specific adverse events outcome | Number of studies (participants) | Summary of effects | Overall certainty of the evidence | Interpretation of findings |
| Postural orthostatic tachycardia syndrome (POTS) | Two cohort studies (1,058,868 person‐years) One self‐controlled case series (1619 person‐years) |
The cohort studies reported no association between HPV vaccination and POTS (RR 0.99, 95% CI 0.46 to 2.22). The self‐controlled case series reported no increased risk of POTS following HPV vaccination. |
MODERATEa
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination likely does not increase the risk of POTS. |
| Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) | Four cohort studies (4,336,406 person‐years) Three self‐controlled case series (297 cases) Two pre‐post vaccine introduction studies (509,331 person‐years) |
The cohort studies reported no association between HPV vaccination and CFS/ME (RR 0.96, 95% CI 0.67 to 1.39). Some studies found that HPV vaccination was associated with a lower likelihood of CFS/ME. The self‐controlled case series analyses reported no increased risk of CFS/ME following HPV vaccination (RR 0.74, 95% CI 0.40 to 1.39). The pre‐post vaccine introduction studies reported no increase in the incidence of CFS/ME following introduction of HPV vaccine. |
MODERATEb
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination likely does not increase the risk of CFS/ME. |
| Paralysis | Five cohort studies (24,663,514 person‐years) One self‐controlled case series (33 cases) |
The cohort studies reported no association between HPV vaccination and increased risk of paralysis (RR 0.62, 95% CI 0.36 to 1.07). Some studies found that HPV vaccination was associated with a lower likelihood of paralysis. The self‐controlled case series reported no increased risk of paralysis following HPV vaccination. |
MODERATE c
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination likely does not increase the risk of paralysis. |
| Complex regional pain syndrome (CRPS) | Three cohort studies (3,330,138 person‐years) One self‐controlled case series (535 cases) |
The cohort studies reported no association between HPV vaccination and CRPS (RR 0.76, 95% CI 0.62 to 0.94). The self‐controlled case series reported no increased risk of CRPS following HPV vaccination. |
MODERATE d
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination likely does not increase the risk of CRPS. |
| Guillain‐Barré syndrome | Ten cohort studies (42,442,906 person‐years) One case‐control study (0 cases/143 females) Three self‐controlled case series (156 cases) One pre‐post vaccine introduction study (876,492 females and males) |
Nine of the cohort studies reported no association between HPV vaccination and increased risk of Guillain‐Barré syndrome (RR 0.89, 95% CI 0.36 to 2.20). One reported an increase in incidence associated with HPV vaccination. Some studies found that HPV vaccination was associated with a lower likelihood of Guillain‐Barré syndrome. The case‐control study reported no cases of Guillain‐Barré syndrome. The self‐controlled case series analyses reported no increased risk of Guillain‐Barré syndrome following HPV vaccination (RR 1.53, 95% CI 0.78 to 2.98). The pre‐post vaccine introduction study reported no increase in the incidence of Guillain‐Barré syndrome following HPV vaccination. |
LOWe,f
⊕⊕◯◯ Downgraded due to methodological limitations and inconsistency |
The evidence suggests that HPV vaccination does not increase the risk of Guillain‐Barré syndrome. |
| Premature ovarian failure | Three cohort studies (996,428 females plus 2,774,964 person‐years) | The cohort studies reported no association between HPV vaccination and premature ovarian failure. | MODERATEg
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination likely does not increase the risk of premature ovarian failure. |
| Infertility | One cohort study (3483 females, 1022 males) One cross‐sectional study (1114 females) |
The cohort study reported no association between HPV vaccination and fecundability in females or males. The cross‐sectional study reported no association between HPV vaccination and infertility in females. |
MODERATEh
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination likely does not increase the risk of infertility. |
| Sexual activity | Three cohort studies (1968 females) Two cross‐sectional studies (209,586 females) One pre‐post vaccine introduction study (260,493 females) |
The cohort studies reported no association between HPV vaccination and sexual activity, measured as incidence of sexually transmitted infections. The cross‐sectional studies reported no association between HPV vaccination and sexual activity, measured as incidence of sexually transmitted infections. The pre‐post vaccine introduction study reported no association between HPV vaccination and sexual activity, measured as incidence of sexually transmitted infections. |
MODERATEi
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination likely does not increase sexual activity and the incidence of sexually transmitted infections. |
CFS/ME: chronic fatigue syndrome/myalgic encephalomyelitis; CI: confidence interval; CRPS: complex regional pain syndrome; HPV: human papillomavirus; POTS: postural orthostatic tachycardia syndrome; RR: risk ratio
aOne cohort study was at moderate risk of bias, one at serious risk. The main concerns for bias were the potential for residual confounding and selective reporting. The self‐controlled case series was at low risk of bias. Overall, we have downgraded one level for methodological limitations.
bThe cohort studies were at moderate or serious risk of bias. The main concern for bias was the potential for residual confounding. The self‐controlled case series were at low risk of bias. Overall, we have downgraded one level for methodological limitations.
cThe cohort studies were at moderate or serious risk of bias. The main concern for bias was the potential for residual confounding. Overall, we have downgraded one level for methodological limitations.
dAll three cohort studies were at serious risk of bias. The main concerns for bias were the potential for residual confounding and measurement of the outcome. The self‐controlled case series was at low risk of bias. Overall, we have downgraded one level for methodological limitations.
eThe cohort studies were at serious or critical risk of bias. The main concern for bias was the potential for residual confounding. The self‐controlled case series were at low risk of bias. Overall, we have downgraded one level for methodological limitations.
fDowngraded one level for inconsistency – studies show no effect, a possible harm and a possible benefit of HPV vaccination.
gThe cohort studies were at moderate to critical risk of bias. The main concerns for bias were the potential for residual confounding and selection bias. Overall, we have downgraded one level for methodological limitations.
hBoth studies were at serious risk of bias. The main concerns for bias were the potential for residual confounding, classification of the interventions and missing data. Overall, we have downgraded one level for methodological limitations.
iThe cohort studies were at serious or critical risk of bias. The main concern for bias was the potential for residual confounding. Overall, we have downgraded one level for methodological limitations.
Background
Description of the condition
Cervical cancer is the fourth most common cancer and the fourth leading cause of death from cancer amongst females worldwide, with an estimated 570,000 new cases and 311,000 deaths in 2018 (Bray 2018). Cervical cancer is a common cancer in young women and people with a uterine cervix, particularly in the 25 to 45 age group (Bray 2018). The risk of developing cervical cancer by age 65 years ranges from 0.8% in developed countries to 1.5% in developing countries, and more than 85% of all cervical cancer deaths occur in low‐ and middle‐income countries (LMIC) (Bray 2018). The large geographical variation in cervical cancer rates and survival correlates with the availability of primary and secondary prevention strategies, as well as the prevalence of high‐risk human papillomavirus (hrHPV) infection. However, even in the UK, with a world‐leading screening programme, cervical cancer in females aged 25 to 49 is the fourth highest cause of cancer death (Cancer Research UK 2024b). In England, 4.63 million women were invited for cervical screening in a year (2019 to 2020), in order to identify and treat those at higher risk of cervical cancer (NHS Digital 2020a). Of these, nearly 100,000 required further investigation with colposcopy (direct visualisation of the cervix with a microscope) to determine whether treatment was needed for cervical intra‐epithelial neoplasia (CIN) or, more rarely, cervical glandular intraepithelial neoplasia (CGIN ‐ also known as adenocarcinoma in situ (AIS)) precursor lesions to prevent cervical cancer (NHS Digital 2020b). This can cause anxiety and distress for many people. Furthermore, treatment for CIN, although relatively minor and straightforward in most cases, may put some people at higher risk of premature birth, thereby having long‐term knock‐on effects of preventative treatment (Kyrgiou 2017).
Human papillomavirus (HPV) is the most common viral infection of the reproductive tract (WHO 2017). Infection with hrHPV is necessary, but not sufficient to develop cervical cancer. The majority of people are exposed to hrHPV and, although most HPV infections resolve spontaneously (Insinga 2011), persistent infections can lead to precancerous lesions and cancer of the cervix, vagina, vulva, anus, penis, and head and neck. In 2012, HPV‐related cancers accounted for an estimated 4.5% of all cancers worldwide (De Martel 2017). Of these estimated 636,000 HPV‐related cancers, 530,000 were cervical cancer, 35,000 anal cancer, 8500 vulval cancer, 13,000 penile cancer and 37,000 head and neck cancers (De Martel 2017).
Anogenital warts are caused by non‐oncogenic HPV subtypes, with HPV 6 and 11 responsible for 90% (Hawkins 2013). Anogenital warts are highly transmissible and difficult to eradicate, with high recurrence rates. The cost of treatment of anogenital warts in England in 2008 was estimated to be GBP 16.8 million, contributing to 6.6 days of healthy life lost per episode (Desai 2011; Woodhall 2011), and USD 220 million in the USA in 2004 (Insinga 2005). A systematic review found that annual incidence rates of new and recurrent anogenital warts, from clinical studies, vary from 160 to 289 per 100,000 (Patel 2013). Incidence is higher in those with immunocompromise, including immunosuppression following organ transplantation and HIV infection, and in men who have sex with men (MSM), with 11.6% of MSM reporting anogenital warts in a UK‐based study (Sonnenberg 2019). Many studies included in the systematic review came from high‐income countries. However, in one study from Nigeria, the incidence of anogenital warts was 1% in HIV‐negative women, and 5% in HIV‐positive women, demonstrating a significant health burden, especially in LMICs, which can have a profound effect upon quality of life (Dareng 2019).
With the advent of immunisation and screening programmes in developed countries, the majority of invasive cervical cancers could be prevented (Cancer Research UK 2024a). In 2018, The World Health Organization (WHO) Director‐General made a global call for the elimination of cervical cancer (Adhanom‐Ghebreyesus 2018). However, in the absence of organised screening, many people present with symptoms and locally advanced cervical cancer at diagnosis (WHO 2018). Sadly, even in countries with well‐organised, freely available screening programmes, screening cannot prevent all cervical cancers and is not widely accessible globally. Cervical cancer therefore remains a significant disease. Furthermore, ~20% of HPV‐related cancers do not have effective screening methods.
The introduction of primary testing for hrHPV, compared to cervical cytology, improves the sensitivity of screening, albeit at the cost of increased referrals to colposcopy (Koliopoulos 2017). This leads to an increase in the rate of detection of CIN and is likely to reduce the rate of cervical cancer within a population over time. However, unless background rates of hrHPV and high‐grade CIN also fall, this will increase the treatment rates for CIN.
Description of the intervention
HPV vaccines were first licenced in 2006, and by 2016, 55% of high (HIC) and upper‐middle‐income (UMIC) countries had introduced vaccination programmes, compared to just 14% of lower‐middle‐income (LMIC) and lower‐income (LIC) countries, where disease burden of cervical cancer is higher, according to World Bank figures (Gallagher 2018; LaMontagne 2017).
The uptake of HPV vaccination varies widely between countries: in 2017, coverage rates ranged from 8% to 98% across 82 countries (Brotherton 2018). WHO estimated only 13% global HPV vaccine coverage in 2020, a reduction from 15% in 2019, despite the vaccine being available since 2006 (WHO 2021a). Reasons for this variation include organisation of immunisation programmes, resistance from healthcare providers, adverse media coverage and concerns about safety (Gallagher 2018).
Four prophylactic HPV vaccines have been pre‐qualified by WHO (see Table 3). Each vaccine is directed against two or more high‐risk HPV genotypes. All four vaccines contain L1 proteins of HPV genotypes 16 and 18 (Qiao 2020; WHO 2017), because these cause about 70% of cervical cancer globally. In addition to the pre‐qualified vaccines, as of December 2021, there are two vaccines in stage 2 to 3 development, one bivalent vaccine manufactured by Walvax in China, and a quadrivalent vaccine manufactured by the Serum Institute of India (LaMontagne 2017).
1. Characteristics of WHO pre‐qualified prophylactic HPV vaccines.
| Cervarix | Gardasil | Gardasil 9 | Cecolin | |
| Manufacturer | GlaxoSmithKline (GSK, Rixensart, Belgium) | Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA) | Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA) | Xiamen Innovax Biotech Co. Ltd. (Xiamen, Fujian province, China) |
| Antigens | Bivalent: L1 VLPs of HPV16 (20 μg) and HPV18 (20 μg) | Quadrivalent: L1 VLPs of HPV6 (20 μg), HPV11 (40 μg), HPV16 (40 μg) and HPV18 (20 mg) | Nonavalent: L1 VLPs of HPV6 (30 μg), HPV11 (40 μg), HPV16 (60 μg), HPV18 (40 μg), HPV31 (20 μg), HPV33 (20 μg), HPV45 (20 μg), HPV52 (20 μg) and HPV58 (20 μg) | Bivalent: L1 VLPs of HPV16 (40 μg) and HPV18 (20 μg) |
| Vaccination schedule | 3 doses: at day 1, month 1 and month 6 | 3 doses: at day 1, month 2 and month 6 | 3 doses: at day 1, month 2 and month 6 | 2 doses: at day 1 and month 6 |
| Adjuvant | AS04: 500 μg aluminium hydroxide, 50 μg 3‐deacylated monophosphoryl lipid A (MPL) | 225 μg amorphous aluminium hydroxyl‐phosphate sulphate | 500 μg amorphous aluminium hydroxyl‐phosphate sulphate | 208 μg aluminium adjuvant |
| Trade name | Cervarix | Gardasil, Silgard | Gardasil‐9 | Cecolin |
| Produced by recombinant technology using | Baculovirus in Trichoplusia in insect cells | Saccharomyces cerevisae (Baker’s yeast) | Saccharomyces cerevisae (Baker’s yeast) | Escherichia coli |
HPV: human papillomavirus; VLP: virus‐like particles; WHO: World Health Organization
How the intervention might work
HPV L1 coat proteins self‐assemble into virus‐like particles (VLP), empty virus particles (capsids), containing no virus DNA (Kirnbauer 1992), which cannot cause an active infection. They work as prophylactic vaccines, which means they prevent an initial infection by HPV, in turn preventing the development of intraepithelial lesions caused by HPV genotypes that are present in the vaccine (Stanley 2006). HPV vaccines are therefore less effective in those already exposed to HPV (Arbyn 2018), hence why they are offered to adolescents, aiming for immunity prior to onset of sexual activity.
The virus‐like particles in the vaccines produce very high levels of antibodies in blood samples. The International Agency for Research on Cancer regards persistent HPV infection with HPV types 16 and 18 as an accurate surrogate marker for the development of precancerous lesions of the cervix and anus (IARC 2014). Persistent infection with hrHPV is the main cause of cervical cancer (Bosch 2002; Jaisamrarn 2013; Munoz 1996), with a well‐recognised progression from persistent HPV infection to the development of cervical intraepithelial neoplasia (CIN), although the majority of infections are cleared spontaneously and do not cause persistent infection (Insinga 2011). However, left untreated, almost one in three of those with high‐grade CIN (CIN3) will go on to develop cancer over 8 to 15 years (Campbell 1989; McIndoe 1984). It was therefore assumed that prevention of precancerous lesions would also be shown to prevent cancer when sufficient follow‐up time has accrued in post‐licensure studies. Less is known about the prognostic value of persistent HPV infection in the development of vaginal, vulval and oropharyngeal cancers (IARC 2014).
Why it is important to do this review
Prevention or early detection of cancer is a major priority within health care, especially within the UK where survival rates lag behind European counterparts, largely due to late detection (De Angelis 2014). In cervical cancer, we are fortunate as the main focus is on prevention, since, unlike many cancers, it can be prevented or detected at a pre‐invasive stage. HPV vaccination, especially in countries where screening programmes are currently unaffordable, has the potential to be transformative.
Although conventional Cochrane reviews of randomised controlled trials (RCTs) have demonstrated the effectiveness of HPV vaccination (Arbyn 2018; Bergman 2025), due to the relatively short time periods of the studies, effective screening and follow‐up of those in the studies, the outcome measures are surrogate endpoints, rather than cervical cancer outcomes. As HPV can cause a variety of cancers in both males and females, short‐term RCTs are unlikely to capture the population‐level benefits of HPV vaccination, especially in un‐ or under‐screened individuals and populations. Additionally, even very large RCTs are unlikely to be able to fully evaluate rare and very rare adverse events, of treatment or non‐treatment, including those later events, such as premature delivery of infants due to treatment of CIN, which could otherwise have been avoided (Kyrgiou 2017), and prevention of long‐term complications from cancer treatment, such as lymphoedema and late effects of radiotherapy. Furthermore, benefits of vaccination in a population may extend out to non‐vaccinated individuals, if vaccination levels are high enough, due to the development of herd immunity, by reducing the prevalence of an infection in a population. Larger, population‐level, non‐randomised studies (NRS) are therefore better able to inform of the absolute harms and benefits of HPV vaccination, beyond that of selected trial participants. Outcome data on long‐term effects of HPV vaccination are now becoming available and recent studies demonstrate improvement in both cervical cancer rates and preterm delivery rates in HPV vaccinated cohorts (Aldhous 2019; Falcaro 2021; Lei 2020). The full impact of HPV vaccination on cancer incidence will not be known for many years, since the natural history of vulval, penile and head and neck cancers, caused by hrHPV, is much longer.
Evaluating the longer‐term harms and benefits of HPV vaccination is extremely important, especially in the face of community concerns about these issues, which can fuel vaccine hesitancy (Karafillakis 2019; Wong 2020). Scares about adverse events can be catastrophic to a vaccination programme. For example, in Denmark and Ireland, community scares saw vaccination rates temporarily drop from over 80% to around 50% (Corcoran 2018; Suppli 2018). In Japan, a scare also resulted in a pause in government recommendation of vaccination (Ujiie 2022).
With the global reach of social media, dissemination of information regarding adverse effects of vaccination can be extremely pervasive. It is therefore extremely important to more fully evaluate these outcomes, to provide reliable data to young people, parents, clinicians, policymakers and others when they are making choices about vaccination.
A comprehensive examination of the rare risks, and a better understanding of the longer‐term benefits of HPV vaccination, such as effects on cancer rates, preterm birth rates and reduced complications due to falling need for treatment of CIN, require large data from population‐level studies. It is hoped that these data will better inform the public debate about the benefits and harms of HPV vaccination and allow better‐informed decision‐making.
This review will look at non‐randomised studies of the effects of introducing HPV vaccination at a population‐level on rates of HPV‐related disease and harms, not just in the individuals vaccinated, thereby more fully informing the harms and benefits of vaccination, which may not be apparent even in large RCT‐level datasets (Reeves 2022). We evaluate RCTs in a parallel Cochrane review (Bergman 2025). It is hoped that these reviews will better inform the public debate about the benefits and harms of HPV vaccination and allow better decision‐making at an individual level.
Objectives
We aimed to assess population‐level effects of human papillomavirus (HPV) vaccination programmes on HPV‐related disease and harms from vaccination.
Methods
Criteria for considering studies for this review
Types of studies
We included studies that assessed the impact of HPV vaccination on the general population. This included population‐level studies comparing outcomes before and after introduction of HPV vaccine, such as pre‐ versus post‐vaccine introduction studies, interrupted time series studies and controlled before‐and‐after studies. We also included individual‐level, non‐randomised comparative studies such as cohort studies, case‐control studies and self‐controlled case series. This included follow‐up of cohorts that were originally included in randomised controlled trials (RCTs). We did not include non‐comparative studies, such as single‐arm cohorts, case series or case reports, nor modelling studies, or RCTs. We included studies that were self‐described as the above designs; however, the final decision on the design was made by the review author team. Working definitions for the different study designs are provided in Appendix 1.
RCTs were not included, as these are assessed in a companion review (Bergman 2025).
Types of participants
The target population for HPV vaccination is adolescents, although some countries also vaccinate adults. We have included studies on all ages receiving prophylactic HPV vaccination. Studies on the general population were included and, where possible, we stratified analyses by age at vaccination and sex. Studies with only a subset of eligible participants were included if the eligible participants made up > 75% of the total population.
Types of interventions
We investigated primary prophylactic administration of HPV vaccines pre‐qualified by WHO (WHO 2021b), including Cervarix (bivalent, GlaxoSmithKline), Gardasil (quadrivalent, Merck), Gardasil‐9 (nonavalent, Merck) or Cecolin (bivalent, Innovax) HPV vaccines (see Table 3). We included studies evaluating the effect of a full vaccine series (three doses) or partial vaccine series (one or two doses). We excluded studies assessing non‐prophylactic and secondary prevention (i.e. used to prevent recurrence in those treated for HPV‐related disease) uses of vaccines.
We included studies that compare vaccination with any of the HPV vaccines with no vaccination. We investigated partial vaccination schedules compared with no vaccination using subgroup analysis.
Types of outcome measures
Whilst we recognise the importance of serious adverse events (those causing death, disability or hospitalisation), we also realise the importance of those adverse events perceived by patients as most prevalent and those adverse events that may prevent uptake. Prior to this review, we therefore conducted surveillance of the social media platforms WebMD and X (formerly Twitter) for important specific adverse events (see Appendix 2). We identified reports of 276 adverse events on WebMD, which we analysed by frequency and added pertinent adverse events to our strategy. We also identified 9781 tweets on HPV and found that injury was the top mentioned adverse event (51%), followed by death (23%), similar adverse events to those in WebMD, and concern about the potential for HPV vaccination to promote sexual promiscuity.
Any measure of the outcomes below was considered eligible for inclusion. While the duration and completeness of follow‐up varies, we extracted all relevant outcomes and time points reported. We stratified all analyses by outcome time point since vaccination as immediate term (< 4 weeks), short term (< 1 year), medium term (1 to 5 years) and long term (> 5 years). The lists of outcomes below are not exhaustive of all relevant outcomes for HPV vaccination. We excluded studies that did not report on any of the outcomes on the list, such as antibody titres, seroconversion or other specific adverse events.
Primary outcomes
Invasive cervical, vaginal, vulval, anal, penile, or head and neck cancer rates.
In females, histologically confirmed high‐grade cervical (CIN2, CIN3 and adenocarcinoma in situ (AIS)), vaginal (VaIN), vulval (VIN) or anal intraepithelial neoplasia (AIN), irrespective of HPV genotype (precancers of the cervix, vagina, vulval and anal skin/surface layers).
In males, histologically confirmed penile (PeIN) or anal (AIN) intraepithelial neoplasia of any grade irrespective of HPV genotype (precancers of the penile and anal skin).
Specific adverse events: incidence of postural tachycardia syndrome (POTS); chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME); paralysis; complex regional pain syndrome (CRPS); premature ovarian failure (POF); Guillain‐Barré syndrome (GBS); infertility; indicators of sexual activity.
Secondary outcomes
Participation rates in cervical screening.
Treatment rates for CIN and other HPV‐related pre‐invasive disease.
Anogenital warts.
In females, miscarriage and pre‐term birth rates, and neonatal outcomes.
All‐cause mortality.
Serious adverse events (that are fatal, life‐threatening, result in hospitalisation, persistent or significant disability/incapacity, congenital anomaly/birth defect, or require intervention to prevent permanent impairment or damage) (FDA 2024).
Incident infection with vaccine HPV genotypes (HPV 16 and HPV 18, jointly; HPV 6, HPV 11, HPV 16 and HPV 18, jointly; and HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58, jointly).
Persistent infection (persisting for at least six months or at least 12 months) with vaccine HPV genotypes (HPV 16 and HPV 18, jointly; HPV 6, HPV 11, HPV 16 and HPV 18, jointly; and HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58, jointly).
Prevalent infection with vaccine HPV genotypes (HPV 16 and HPV 18, jointly; HPV 6, HPV 11, HPV 16 and HPV 18, jointly; HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58, jointly; and HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58, jointly).
It should be noted that POTS, CFS/ME and CRPS are diagnoses of exclusion, and global population background rates are not well‐established. We therefore sought to ascertain rates of these and other specific diagnoses, rather than rely on a constellation of symptoms that might or might not be indicative of these rare syndromes.
Search methods for identification of studies
We attempted to identify all relevant studies regardless of language or publication status (published, unpublished, in press and in progress).
Electronic searches
The Information Specialist at the Cochrane Gynaecological, Neuro‐oncology and Orphan Cancers group designed the search strategies and ran the searches in the core databases:
the Cochrane Central Register of Controlled Trials (CENTRAL; 2022, Issue 1), in the Cochrane Library;
MEDLINE Ovid (2000 to 5 January 2022);
Embase Ovid (2000 to 5 January 2022).
Due to the timeline of HPV vaccine development, searches earlier than 2000 were not required. An update search was performed in the above databases on 11 September 2024.
We have presented the MEDLINE search strategy in Appendix 3, which reflects the key concepts of the review. We adapted the MEDLINE search strategy, as indicated, for the other databases (Appendix 4; Appendix 5).
We did not apply language restrictions to the electronic searches, and arranged for translations as needed. If relevant studies were only reported in abstract form, we contacted the study authors for additional information when necessary.
Searching other resources
We searched the following databases for related systematic reviews and ongoing studies, and checked the reference lists of those that were relevant, for additional studies:
Epistemonikos: https://www.epistemonikos.org;
HTA Database (Health Technology Assessments Database): www.york.ac.uk/crd/#HTA.
We handsearched abstract books of meetings of the International Gynaecological Cancer Society, the European Society of Gynaecological Oncology, International Papillomavirus Meetings, EUROGIN (EUropean Research Organisation on Genital Infection and Neoplasia) and the Society of Gynecologic Oncologists from 2010 to the latest edition, to identify ongoing and unpublished studies. Where necessary, we contacted the main investigators of relevant ongoing studies for further information.
Abstracts of the Society of Gynecologic Oncology (SGO) Annual Meetings on Women’s Cancer are published in Gynecologic Oncology and were accessed by our electronic searches.
We also searched vaccine manufacturer websites for any relevant non‐randomised studies (NRS) and checked the reference list from an index of HPV studies (Jørgensen 2020).
Data collection and analysis
We uploaded the results of all searches to DistillerSR (DistillerSR 2021) to aid sifting and remote teamwork. We used Review Manager (RevMan) for review production (RevMan 2025), using standard Cochrane methods.
Selection of studies
Citations and abstracts were screened independently, in duplicate, by two systematic review team members or by the Cochrane Crowd and one of our systematic review team members. A third review author resolved any disagreements. Cochrane Crowd is Cochrane’s citizen science platform, hosting citation screening tasks. Evaluations of Crowd accuracy have shown very high levels of sensitivity (99%) and specificity (99%) for RCTs (Noel‐Storr 2021). We developed a learning module and agreement algorithm for the Crowd to screen for NRS. We obtained full‐text reports for all potentially eligible studies. Two independent review authors determined the eligibility of studies for inclusion in the review from the full reports according to predefined criteria. A third systematic review author resolved any disagreements.
We checked all studies for potential overlapping populations. We considered populations to be overlapping if two studies included people in the same region during overlapping time periods, and it was likely that their data were reported in both studies. In this case, we grouped these studies together under the same study name in the list of included studies and only included one study in the meta‐analysis if the studies reported on the same outcomes. This was the study with the most comprehensive coverage of the population.
Data extraction and management
Two review authors carried out data extraction independently using pretested data extraction forms. Study characteristics and outcome data were independently extracted, and we resolved any differences by discussion between the two review authors and referral to the study reports. Where there were two or more sources of data with conflicting information, we noted the conflict and attempted to contact the study authors for clarification. We had planned to contact study authors for missing data but did not identify any missing information.
Outcome data and confounders
We collected outcome definitions, source of outcome data and duration since vaccination for each outcome.
We collected the number of participants experiencing an outcome event and the number of participants analysed in each group. Where only rates were reported, we collected the event rate or the number of events and the person‐years in each intervention group. Where available, we extracted adjusted effect estimates with their respective measure of variance (standard error (SE), standard deviation (SD) or 95% confidence interval (95% CI)). We collected data on any confounding factors considered in the analysis and the methods used to control for confounding.
We preferentially extracted outcomes assessed by the most clinically valid measure and effect estimates adjusted for the most confounders.
We assessed whether there was targeted ascertainment of pre‐specified participant outcomes, or if the information had to be extracted from routine healthcare administrative or insurance databases.
Study characteristics
We recorded information on the following study characteristics.
Methods: study design, study dates, duration of follow‐up, source of data.
Setting: country and location, country income level (high‐ (HIC), upper‐middle‐ (UMIC), lower‐middle‐ (LMIC), or low‐income country (LIC) using World Bank classifications) (World Bank 2024).
Population: sample size, sex, sexual orientation, age at vaccination, age at outcome collection, morbidities and socioeconomic status.
Intervention: vaccine type, vaccination schedule (doses, interval), start date of vaccination programme, participation rates in vaccination HPV programme and co‐interventions (i.e. type (primary HPV versus cytological with or without HPV‐triage) and participation rates of cervical screening programme in the population).
Notes: source of funding, conflicts of interest of study authors.
Assessment of risk of bias in included studies
We assessed the risk of bias of all included outcome effect estimates using different tools according to study design. For NRS of interventions, e.g. cohort, case‐control, cross‐sectional and pre‐post vaccine introduction studies, we used the ROBINS‐I tool for each outcome (Sterne 2016; Sterne 2021). In the ROBINS‐I tool, the following risks of bias are assessed: confounding, selection bias, bias in classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes and bias in selection of the reported result. We considered the effect of assignment to the intervention as our effect of interest. For other study designs, such as self‐controlled case series, we used different methodological quality checklists based on the key sources of bias (Farrington 2004; Petersen 2016).
Two review authors independently assessed the risk of bias of each result included in the summary of findings tables. Any disagreements were resolved through discussion, and if consensus could not be reached, a third review author made the final assessment. Following assessment of all included studies, reliability and consistency of ratings across the studies was ensured through discussion among the review team. Any further disagreements were resolved through discussion within the review team.
As part of the risk of bias assessment, a preliminary specification of important confounders and co‐interventions was made using directed acyclic graphs (Suttorp 2015). These confounders and co‐interventions were derived from the adjustment and stratification variables used in analyses of known studies, variables mentioned or used in relevant systematic reviews (Drolet 2019; Markowitz 2018), and variables used in an ongoing living systematic review assessing risk of bias in observational studies on COVID vaccines (COVID NMA 2024).
We considered the most important confounding domains to be as follows.
Time‐fixed confounders
Age
Sex
Socioeconomic status
Ethnicity
Geographic location
Preventive health‐seeking behaviour
Time‐varying confounders
Calendar time (to reflect changing incidence of virus and time since vaccine introduction)
We considered the most important co‐intervention to be the presence of a cervical cancer screening programme in the country in which the study was conducted.
The results of the risk of bias assessments are summarised and provide an evaluation of the overall methodological quality of the included studies. They also contributed to the GRADE ratings of the certainty of the evidence on an outcome basis.
Measures of treatment effect
Where data permitted, we combined adjusted point estimates using risk ratios (RR), odds ratios (OR), hazard ratios (HR) or relative incidence (RI) and their 95% CIs. We used the generic inverse variance method in RevMan Web (DerSimonian and Laird random‐effects).
If several adjusted estimates were reported within a study, we gave preference to the estimate that adjusts for the most important confounders that we pre‐specified for the review.
Unit of analysis issues
Unit of analysis issues were not expected. We analysed partial and full vaccination separately.
Dealing with missing data
We did not impute missing outcome data. Where missing data were substantial (> 5%), we assessed the risk of bias due to missing outcome data with the ROBINS‐I tool as moderate or serious risk (Sterne 2016).
Clinical and methodological heterogeneity
We did not pool data from different study designs. Analyses are stratified by study design, type of vaccine, age at vaccination and sex. If these characteristics were mixed or unknown within a study and could not be disaggregated, we analysed studies in a mixed group. Potential sources of heterogeneity are described, and the certainty of the evidence downgraded according to GRADE criteria, where appropriate.
Statistical heterogeneity
When pooling of studies was feasible (at least two studies included), we visually inspected forest plots for potential outlying studies and variability in the estimated effects across studies. We assessed statistical heterogeneity using the I2 statistic. This statistic quantifies the percentage of inconsistency in the treatment effects across studies beyond simple chance.
Assessment of reporting biases
For all included studies, we searched for published or online study protocols or statistical analysis plans. We recorded the presence or absence of these in the study characteristics tables and addressed this with the risk of bias tools. Where studies did not explicitly report on outcomes, we did not consider them at risk of selective reporting, unless there was evidence that they were planned and omitted from the report.
Data synthesis
The inclusion of various study designs in this review that use different estimation methods and statistical models means that we calculated different measures of effect and interpret these separately. We carried out quantitative and qualitative data syntheses separately for effectiveness and safety (harms).
We grouped studies for quantitative analysis according to study design (see Types of studies and Appendix 1) and outcome. Where possible, we stratified analyses by age at vaccination, sex, type of vaccine and outcome time point. We analysed all outcomes according to time from first vaccination, considering immediate term to be less than 4 weeks, short term to be less than 12 months, medium term from 12 months to 5 years, and long term for follow‐up longer than 5 years. If a study reported multiple time points within these categories, we prioritised the longest time point for meta‐analysis.
To account for confounding, if both adjusted and unadjusted estimates were reported within a study, we gave preference to the estimate that adjusted for the most important confounders for the review. Where data permitted, we combined adjusted point estimates using the generic inverse variance method (DerSimonian and Laird random‐effects). We also performed an analysis of adjusted effect estimates from those in the target population for vaccination, i.e. ≤ 16 years of age.
We checked all observational studies for potential overlapping populations, based on the location, study dates and source of the population and outcome data. Where we considered studies to be overlapping, these are grouped together in the list of included studies, and we only included one study in the meta‐analysis. This was the study with the lowest risk of bias, the largest sample size, or that covered the longest time period.
We used RR and its CI as measures of effect for cohort studies and population‐level studies. We used the OR and its CI for case‐control studies. For self‐controlled case series studies, we calculated a RI and its CI.
When meta‐analysis was not possible or appropriate, we used 'Synthesis without meta‐analysis' (SWiM) methodology (Campbell 2020).
Subgroup analysis and investigation of heterogeneity
We were unable to perform our planned subgroup analysis by time since vaccination programme introduction, as this was not clearly reported in most studies. We performed separate analyses for participants in the target population for vaccination, i.e. ≤ 16 years of age. We extracted effect estimates for partial schedule (i.e. one or two doses) and reported these along with full schedule effect estimates for each outcome.
Sensitivity analysis
To test the robustness of the data, we planned to carry out the following sensitivity analyses for the primary outcomes.
We planned to exclude studies with overall critical or serious risk of bias from the analysis. We did not identify any studies that reported effect estimates adjusted for confounding that were considered at critical risk of bias. Most studies were at serious risk of bias, so where possible we have reported in the results which studies are at moderate or low risk of bias. Separate analyses for these studies were not necessary.
We planned to perform meta‐analysis using the Hartung‐Knapp‐Sidik‐Jonkman method when combining unadjusted estimates (IntHout 2014). However, we now only analyse adjusted effect estimates using the generic inverse variance approach.
If we had included any studies reported only as abstracts, we had planned to remove these from the analysis. However, we did not include any studies that were only reported as abstracts.
Summary of findings and assessment of the certainty of the evidence
We prepared summary of findings tables (Schünemann 2021) for HPV vaccination compared with no vaccination, stratified by study design. We assessed the certainty of evidence in the review through discussion between review authors using the GRADE approach with the GRADEpro online software (GRADEpro GDT) for the following outcomes:
In females, invasive cervical, vaginal, vulval, anal, or head and neck cancer rates; histologically confirmed high‐grade cervical (CIN3 and adenocarcinoma in situ (AIS)), vaginal, vulva or anal intraepithelial neoplasia (AIN), irrespective of HPV genotype.
In males, invasive anal, penile, or head and neck cancer rates; histologically confirmed penile (PeIN) or anal (AIN) intraepithelial neoplasia of any grade irrespective of HPV genotype.
For all populations: anogenital warts, serious adverse events.
We created separate summary tables for specific adverse event outcomes, recording the number and type of studies evaluating each adverse event, the number of participants analysed and the estimates of effect comparing vaccination with no vaccination.
NRS started as high‐certainty evidence, and we considered the following factors for downgrading the certainty of the evidence: limitations in the study design (overall risk of bias); inconsistency of results (heterogeneity); indirectness of evidence (applicability); imprecision (few events and wide confidence intervals); and publication bias (Guyatt 2011). In addition, evidence could be upgraded if the pooled estimates revealed a large magnitude of effect or a dose‐response gradient was apparent (Schünemann 2019).
When the certainty of evidence was downgraded, we detailed the reasons in footnotes of the summary of findings tables and summarised these in the quality of the evidence section. Depending on whether evidence was downgraded or not, we rated the certainty of the evidence for each outcome as follows.
High‐certainty evidence indicates that we are very confident that the true effect lies close to that of the estimate of the effect (evidence will not be downgraded).
Moderate‐certainty evidence indicates that we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different (evidence will be downgraded one step for any of the factors described above).
Low‐certainty evidence indicates that our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect (evidence will be downgraded two steps for any of the factors described above).
Very low‐certainty evidence indicates that we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect (evidence will be downgraded three steps for any of the factors described above).
Stakeholder engagement
HPV vaccination is a major target for misinformation, especially targeting parents/carers via social media. We aimed to provide robust and unbiased evidence for patients, clinicians and policymakers, to enable fully informed decision‐making. This Cochrane HPV vaccine population‐level effect review is conducted in parallel with a Cochrane network meta‐analysis of randomised controlled trials (Bergman 2025). These reviews are both high priority for Cochrane and will inform the WHO and national government screening and immunisation strategies at national and global levels. We are aware that this will subject the review authors to significant scrutiny from communities with concerns about vaccination in general, and HPV vaccination specifically, but we are committed to promoting evidence‐based health care and improving outcomes for HPV‐related disease globally.
An Independent Advisory Group (IAG), including consumers, advised on review production and content.
Results
Description of studies
Overall, 225 non‐randomised studies from 347 records were included in this review (Figure 1). The characteristics of individual studies and assessment of risk of bias are presented in the Characteristics of included studies section.
1.
*includes update search n=4722 records (September 2024) not screened by Cochrane Crowd
Results of the search
The initial electronic database searches resulted in 17,049 de‐duplicated records. We retrieved 456 records from additional sources: 407 from the Epistemonikos and HTA databases and 49 records from handsearching. An update search was performed in the electronic databases on 11 September 2024, resulting in an additional 4722 records for screening.
The initial 17,049 records were screened by Cochrane Crowd. These records were categorised as “not relevant” (n = 15,156) or “possibly relevant” (n = 1893) by the Crowd. The review team then screened the abstracts of all 17,505 records from the database search and additional sources, plus 4722 records from the search update. We excluded 21,414 records and retrieved the full texts for the remaining 813 records. We excluded 461 full texts and included 347. Five records are included in the Characteristics of studies awaiting classification section.
See Figure 1 for a flow diagram of the search and screening process.
Included studies
We included 86 cohort studies, four case‐control studies, 46 cross‐sectional studies, 69 pre‐post vaccine introduction studies, five RCT extensions and two self‐controlled case series. Thirteen additional studies reported on more than one type of analysis.
The included studies reported data from 46 countries. Most studies were carried out in the USA (49), the United Kingdom (21), Denmark (18), Australia (18), Canada (14), Japan (13), the Netherlands (eight), Sweden (seven), Italy (seven), Germany (six), Finland (six), Norway (five), France (five) and Spain (four). Two studies were carried out in Switzerland, Portugal, New Zealand, Mongolia, Thailand, Colombia, South Korea, Belgium and Brazil. There was one study each from Argentina, Armenia, Bhutan, Costa Rica, Czech Republic, Fiji, Greece, India, Israel, Luxembourg, Malaysia, Mexico, Paraguay, Russia, Rwanda, Taiwan and Uganda. The remaining eight studies reported data from more than one country, such as Denmark and Sweden (three), Denmark, Norway and Sweden (two), Denmark and Norway (one), Denmark, Iceland, Norway and Sweden (one), and Bhutan and Rwanda (one).
Of the included studies, 177 reported on only females, 10 only males and 37 a combination of males and females. One study reported on a sample of men who have sex with men and transgender females (Winer 2021‐USA).
Thirty‐two of the included studies reported on the effect of Cervarix vaccine, 131 reported on Gardasil, one reported on Gardasil‐9 and 47 reported on the effect of more than one of these vaccines. In 14 studies it was not clear which vaccine was being evaluated. We did not identify any studies reporting on the effectiveness of the Cecolin vaccine.
Many of the included studies reported on more than one outcome of interest. There were 20 studies reporting on cervical cancer, three studies on vaginal cancer, five studies on vulval cancer, three studies on anal cancer, two on penile cancer, and five studies on head and neck cancer. Three studies reported on adenocarcinoma in situ, 23 studies reported on CIN3+, 13 studies reported on CIN3, 37 studies reported on CIN2+, 11 studies reported on CIN2, two studies each reported on VIN and AIN, and one study reported on VaIN. No studies were identified that reported on population rates of PeIN.
For the specific adverse event outcomes, three studies reported on POTS; eight studies reported on CFS/ME; five studies reported on paralysis; four studies reported on CRPS; three studies reported on POF; 13 studies reported on GBS; two studies reported on infertility; and six studies reported on indicators of sexual activity.
Of the secondary outcomes, 10 studies reported on participation rates in cervical screening; five studies reported on treatment rates; 47 studies reported on anogenital warts; eight studies reported on pregnancy and neonatal outcomes; two studies reported on all‐cause mortality; seven studies reported on incident HPV infection; five on persistent HPV infection; and 80 on prevalent HPV infection. No studies reported on population rates of serious adverse events following HPV vaccination.
Excluded studies
We excluded 461 full texts. Of these, 178 were potentially relevant studies, and the reasons for their exclusion are included in the Characteristics of excluded studies table. We excluded 24 studies because they did not assess a relevant population. Most of the excluded studies (n = 83) contained no relevant outcomes or useable data for the review. We excluded 43 studies because they did not have a relevant comparison and 28 because of an irrelevant study design.
Risk of bias in included studies
We assessed risk of bias for all primary and secondary outcomes using the ROBINS‐I tool (Sterne 2016) or a checklist for self‐controlled case series (SCCS) (Farrington 2004; Petersen 2016). Full details can be found in the additional tables.
Cancer and intraepithelial neoplasia outcomes
Of 20 studies reporting on cervical cancer, nine were at critical risk of bias overall because they failed to control for any potential confounding. Seven studies were at serious risk of bias overall and four were at moderate risk of bias overall. The risk of bias due to confounding was the highest risk domain across the 20 studies, with most other domains at low or moderate risk of bias.
The three studies reporting on adenocarcinoma in situ were all at critical risk of bias overall because they failed to control for any potential confounding. These studies were also at serious risk of selection bias or bias due to classification of the intervention.
Of 23 studies that reported on CIN3+, 10 were at critical risk of bias overall, 12 were at serious risk of bias overall and one study at moderate risk of bias. The bias due to confounding was again at highest risk, with other domains at low or moderate risk of bias.
The three studies that reported on vaginal cancer and five studies that reported on vulval cancer were at serious risk of bias overall due to confounding and bias in the classification of the intervention.
Three studies that reported on anal cancer and penile cancer were at serious risk of bias overall due to confounding and bias in the classification of the intervention.
Five studies reported on head and neck cancer, of which two were at critical risk of bias overall and three at serious risk of bias.
Thirteen studies reported on CIN3, of which 10 were at critical risk of bias due to confounding. Two were at serious risk of bias and one at moderate risk of bias.
Thirty‐seven studies reported on CIN2+, 22 of which were at critical risk of bias overall, 12 at serious risk of bias and three at moderate risk of bias.
Of the 11 studies that reported on CIN2, nine were at critical risk of bias overall and two at serious risk.
One study that reported on VaIN, VIN and AIN was at serious risk of bias overall, one study reporting on AIN was also at serious risk of bias and one study on VIN was at critical risk of bias.
Anogenital warts
Of 47 studies that reported on anogenital warts, 23 were at critical risk of bias overall due to a lack of control of confounding. Twenty‐three studies were at serious risk of bias overall. The domain bias due to confounding was at the highest risk in these studies, with bias in the classification of interventions also at serious risk in many pre‐post vaccine introduction studies. We considered one study at moderate risk of bias overall.
Specific adverse events
Of three studies that reported on POTS, one was at serious risk of bias and one at moderate risk of bias. Both studies controlled for some potential confounders, however the risk of residual confounding remained. One SCCS of POTS was at low risk of bias overall.
Of eight studies that reported on CFS/ME, one was at critical risk of bias, three were at serious risk of bias and two were at moderate risk of bias overall. Three SCCS of CFS/ME were all at low risk of bias overall.
Of five studies that reported on paralysis, four were at serious risk of bias and one at moderate risk of bias. One SCCS of paralysis was at low risk of bias overall.
Three studies reported on CRPS and all were at serious risk of bias overall due to confounding. One SCCS of CRPS was at low risk of bias overall.
Thirteen studies reported on GBS and of these five were at critical risk of bias overall because they did not control for any confounding. Seven studies were at serious risk of bias overall due to the potential for residual confounding. Of three SCCS on GBS, two were at low risk of bias overall and one at moderate risk.
One study on premature ovarian failure was considered at moderate risk of bias overall due to confounding and two studies at critical risk of bias.
Two studies reported on infertility and both were at serious risk of bias overall due to confounding and missing data.
Six studies reported on sexual activity and two were at critical risk of bias due to confounding. Four studies were at serious risk of bias overall due to confounding and bias due to classification of the intervention.
Pregnancy and neonatal outcomes
Eight studies reported on pregnancy and neonatal outcomes; one was at critical risk of bias and seven were at serious risk of bias due to confounding.
All‐cause mortality
Two studies reported on all‐cause mortality, one at critical risk of bias and the other at serious risk due to confounding.
Cervical screening attendance
Of the 10 studies that reported on cervical screening attendance, five were at critical risk of bias overall due to bias from confounding. Four studies were at serious risk of bias overall and one study was at moderate risk of bias.
Treatment rates
Of the five studies that reported on treatment rates for cervical disease, four were at critical risk of bias overall due to confounding. One study was considered at serious risk of bias overall.
Incident HPV infection
Of the seven studies that reported on incident HPV infection, five were considered at serious risk of bias overall and two were at moderate risk of bias overall.
Persistent HPV infection
Of the five studies that reported on persistent HPV infection, three were considered at serious risk of bias overall and two were at moderate risk of bias overall.
Prevalent HPV infection
Of 80 studies that reported on prevalent HPV infection, 31 were at critical risk of bias due to confounding, 46 studies were at serious risk of bias overall and three studies were at moderate risk of bias overall.
Allocation
Not applicable.
Blinding
Not applicable.
Incomplete outcome data
Not applicable.
Selective reporting
Not applicable.
Other potential sources of bias
Not applicable.
Effects of interventions
Primary outcomes
Invasive cervical cancer
See Table 4 for effect estimates and Table 5 for the risk of bias summary of included studies on cervical cancer. HPV vaccination probably reduces the incidence of cervical cancer (moderate‐certainty evidence; Table 1).
2. Primary clinical outcomes effect estimates: invasive cervical cancer.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Del Mistro 2021‐ITA | Gardasil (Merck quadrivalent) | Female, 15 to 25 years | Vaccinated: 4718 Unvaccinated: 91,512 | Risk ratio (long‐term) | 0.92 (0.05 to 15.76) | Unadjusted | Cohort; no events in exposed group |
| Falcaro 2021‐GBR | Gardasil (Merck quadrivalent) | Female, 12 to 13 years | 214,800,000 person‐years; 27,946 cases of cervical cancer |
Incidence rate ratio (long‐term) | 0.13 (0.06 to 0.28) | Age, cohort, age‐by‐cohort interactions, linear trend (drift), dummy variables for the Jade Goody effect (publicity surrounding the last months and death of the celebrity Jade Goody from cervical cancer), seasonal effects, screening awareness campaign | Cohort |
| Falcaro 2021‐GBR | Gardasil (Merck quadrivalent) | Female, 14 to 16 years | 214,800,000 person‐years; 27,946 cases of cervical cancer |
Incidence rate ratio (long‐term) | 0.38 (0.29 to 0.48) | Age, cohort, age‐by‐cohort interactions, linear trend (drift), dummy variables for the Jade Goody effect (publicity surrounding the last months and death of the celebrity Jade Goody from cervical cancer), seasonal effects, screening awareness campaign | Cohort |
| Falcaro 2021‐GBR | Gardasil (Merck quadrivalent) | Female, 16 to 18 years | 214,800,000 person‐years; 27,946 cases of cervical cancer |
Incidence rate ratio (long‐term) | 0.66 (0.59 to 0.75) | Age, cohort, age‐by‐cohort interactions, linear trend (drift), dummy variables for the Jade Goody effect (publicity surrounding the last months and death of the celebrity Jade Goody from cervical cancer), seasonal effects, screening awareness campaign | Cohort |
| Kjaer 2021‐DNK | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, ≤ 16 years | Vaccinated: 502,522 Unvaccinated: 365,167 | Incidence rate ratio (long‐term) | 0.13 (0.04 to 0.40) | Age | Cohort |
| Kjaer 2021‐DNK | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 17 to 19 years | Vaccinated: 502,522 Unvaccinated: 365,167 | Incidence rate ratio (long‐term) | 0.29 (0.08 to 1.01) | Age | Cohort |
| Kjaer 2021‐DNK | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 20 to 30 years | Vaccinated: 502,522 Unvaccinated: 365,167 | Incidence rate ratio (long‐term) | 1.15 (0.88 to 1.50) | Age | Cohort |
| Lei 2020b‐SWE | Gardasil (Merck quadrivalent) | Female, 10 to 16 years | Vaccinated: 527,871 Unvaccinated: 1,145,112 | Incidence rate ratio (long‐term) | 0.12 (0.00 to 0.34) | Age, county of residence, calendar year, mother’s country of birth, parental education level, annual household income, previous diagnosis in mother of CIN3+ or cancers other than cervical cancer | Cohort |
| Lei 2020b‐SWE | Gardasil (Merck quadrivalent) | Female, 17 to 30 years | Vaccinated: 527,871 Unvaccinated: 1,145,112 | Incidence rate ratio (long‐term) | 0.47 (0.27 to 0.75) | Age, county of residence, calendar year, mother’s country of birth, parental education level, annual household income, previous diagnosis in mother of CIN3+ or cancers other than cervical cancer | Cohort |
| Palmer 2024‐GBR | Cervarix (GSK bivalent) | Female, 12 to 13 years at vaccination | Vaccinated: 29,144 Unvaccinated: 294,221 |
Vaccine effectiveness (long‐term) | 100% (66.9% to 100%) | Scottish Index of Multiple Deprivation | Cohort; no events in exposed group |
| Palmer 2024‐GBR | Cervarix (GSK bivalent) | Female, ≥ 14 years at vaccination | Vaccinated: 109,838 Unvaccinated: 294,221 |
Vaccine effectiveness (long‐term) | 73.8% (58.9% to 83.4%) | Scottish Index of Multiple Deprivation | Cohort |
| Ward 2024‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 17 to 18 years* | Vaccinated: 562,899 Unvaccinated: 882,613 |
Vaccine effectiveness (long‐term) | 75.4% (11.4% to 94.6%) | Month of birth | Cohort, regression discontinuity analysis; *age at vaccination |
| Ikeda 2021‐JPN | Cervarix (GSK bivalent; Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Cases: 8 Controls: 12,296 |
Odds ratio (medium‐term) | 0.22 (0.01 to 3.79) | Unadjusted | Case‐control; no events in exposed group |
| Luostarinen 2018‐FIN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 14 to 17 years | N = 189,901 person‐years | Incidence rate ratio (long‐term) | 0.11 (0.01 to 1.93) | Unadjusted | RCT extension; no events in exposed group |
| Rana 2013‐FIN | Gardasil (Merck quadrivalent) | Female, 16 to 17 years | Vaccinated: 3464 person‐years Unvaccinated: 62,878 person‐years |
Incidence rate ratio (medium‐term) | 0.15 (0.01 to 2.47) | Unadjusted | RCT extension; no events in exposed group |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 4348 Unvaccinated: 1574 |
Risk ratio (3 doses; long‐term) | 0.25 (0.01 to 6.01) | Unadjusted | RCT extension; no events in exposed group |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 8431 Unvaccinated: 1574 |
Risk ratio (2 doses; long‐term) | 0.23 (0.01 to 5.60) | Unadjusted | RCT extension; no events in exposed group |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 4950 Unvaccinated: 1574 |
Risk ratio (1 dose; long‐term) | 0.17 (0.01 to 4.25) | Unadjusted | RCT extension; no events in exposed group |
| Dorton 2015‐USA | Gardasil (Merck quadrivalent) | Female, ≤ 26 years |
Vaccinated: 481 Unvaccinated: 911 |
Risk ratio (long‐term) | 1.94 (0.25 to 15.15) | Unadjusted | Cross‐sectional; no events in exposed group |
| Baldur‐Felskov 2015‐DNK | Gardasil (Merck quadrivalent) | Females, 12 to 99 years* | 5567 cases of squamous cell carcinoma |
Annual percentage change (2000‐2005) | ‐0.1% (‐2.6% to 2.4%) | Age‐standardised | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Annual percentage change (2006‐2012) | ‐0.6% (‐3.7% to 2.5%) | ||||||
| Annual percentage change (2013‐2019) | ‐3.9% (‐7.5% to ‐0.2%) | ||||||
| Baldur‐Felskov 2015‐DNK | Gardasil (Merck quadrivalent) | Females, 12 to 99 years* | 1765 cases of adenocarcinoma | Annual percentage change (2000‐2005) | 1.2% (‐0.4% to 2.8%) | Age‐standardised | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Annual percentage change (2006‐2012) | 2.4% (‐2.0% to 7.0%) | ||||||
| Annual percentage change (2013‐2019) | 0.5% (‐3.4% to 4.6%) | ||||||
| Goodman 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 28 to 33 years* | Pre‐vaccine: 22,533 Post‐vaccine: 38,987 |
Relative risk (long‐term; 2013‐2021) | 0.30 (0.14 to 0.65) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Grieger 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 18 to 20 years* | 265,365 cases | Annual percent change (2014‐2018) | ‐2.6% (‐4.4% to ‐0.7%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Grieger 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 21 to 23 years* | 265,365 cases | Annual percent change (2004‐2010) | 13.1 % (4.1% to 22.8%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Annual percent change (2010‐2018) | ‐7.8% (‐12.6% to ‐2.7%) | ||||||
| Grieger 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 24 to 26 years* | 265,365 cases | Annual percent change (2004‐2013) | 9.2% (6.9% to 11.5%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Annual percent change (2013‐2018) | ‐15.4% (‐19.6% to ‐11.1%) | ||||||
| Grieger 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 27 to 29 years* | 265,365 cases | Annual percent change (2004‐2008) | 18.2% (9.4% to 27.7%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Annual percent change (2008‐2015) | 5.0% (0.7% to 9.4%) | ||||||
| Annual percent change (2015‐2018) | ‐15.1 (‐25.9% to ‐4.1%) | ||||||
| Grieger 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 30 to 32 years* | 265,365 cases | Annual percent change (2013‐2018) | ‐2.3% (‐7.7% to 3.4%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Grieger 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 33 to 35 years* | 265,365 cases | Annual percent change (2004‐2013) | 7.3% (5.4% to 9.3%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Annual percent change (2013‐2018) | ‐1.0% (‐5.3% to 3.5%) | ||||||
| Guo 2023‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 24 years at outcome | 1133 cases of cervical carcinoma | Incidence rate ratio (long‐term; 2002‐6 vs 2015‐19) | 0.71 (0.64 to 0.80) | Age‐standardised | Pre‐ vs post‐vaccine introduction |
| Guo 2023‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 34 years at outcome | 16,979 cases of cervical carcinoma | Incidence rate ratio (long‐term; 2002‐6 vs 2015‐19) | 0.91 (0.89 to 0.94) | Age‐standardised | Pre‐ vs post‐vaccine introduction |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Female, age NR | NR | Annual percent change (long‐term; 2000‐2009) | ‐2.5% | Sex, age and delay | Pre‐ vs post‐vaccine introduction |
| Lopez 2018‐ESP | NR | Female, 11 to 14 years | NR | Incidence rate ratio (long‐term; 2003 vs 2014) | 0.83 (0.81 to 0.84) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Onuki 2023‐JPN | NR | Female, 20 to 29 years | 418,918 cases | Annual percentage change (1975‐2011) | 5.9% (5.6% to 6.1%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Annual percentage change (2011‐2020) | ‐13.5% (‐11.9% to ‐14.5%) | ||||||
| Rebolj 2022‐GBR | Cervarix (GSK bivalent) | Female, 24 to 25 years | 32 cases | Vaccine effectiveness (long‐term) | 64% (‐91% to 93%) | Deprivation and laboratory | Pre‐ vs post‐vaccine introduction |
| Restivo 2023‐ITA | NR | Female, age NR | 291,368 cases | Rate ratio (2008 vs 2018) | 0.68 (0.62 to 0.74) | Unadjusted | Pre‐ vs post‐vaccine introduction |
CIN3: cervical intraepithelial neoplasia grade 3; NR: not reported
3. Risk of bias summary: invasive cervical cancer.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Del Mistro 2021‐ITA | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Falcaro 2021‐GBR | Moderate | Low | Low | Low | Low | Low | Low | Moderate |
| Kjaer 2021‐DNK | Serious | Moderate | Low | Low | Low | Low | Moderate | Serious |
| Lei 2020b‐SWE | Moderate | Low | Low | Low | Low | Low | Low | Moderate |
| Palmer 2024‐GBR | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Ward 2024‐GBR | Moderate | Low | Moderate | Low | No information | Low | Low | Moderate |
| Ikeda 2021‐JPN | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Luostarinen 2018‐FIN | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Rana 2013‐FIN | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Sankaranarayanan 2018‐IND | Moderate | Low | Low | Low | Moderate | Low | Low | Moderate |
| Dorton 2015‐USA | Critical | Serious | Moderate | Low | Moderate | Low | Moderate | Critical |
| Baldur‐Felskov 2015‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Goodman 2024‐DEU | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Grieger 2024‐DEU | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Guo 2023‐USA | Serious | Low | Serious | Low | Low | Low | Low | Serious |
| Jemal 2013‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Lopez 2018‐ESP | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Onuki 2023‐JPN | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Restivo 2023‐ITA | Critical | Serious | Serious | Low | Low | Low | Low | Critical |
Twenty studies were included that reported on cervical cancer following HPV vaccination (Baldur‐Felskov 2015‐DNK; Del Mistro 2021‐ITA; Dorton 2015‐USA; Falcaro 2021‐GBR; Goodman 2024‐DEU; Grieger 2024‐DEU; Guo 2023‐USA; Ikeda 2021‐JPN; Jemal 2013‐USA; Kjaer 2021‐DNK; Lei 2020b‐SWE; Lopez 2018‐ESP; Luostarinen 2018‐FIN; Onuki 2023‐JPN; Palmer 2024‐GBR; Rana 2013‐FIN; Rebolj 2022‐GBR; Restivo 2023‐ITA; Sankaranarayanan 2018‐IND; Ward 2024‐GBR).
Six were cohort studies (Del Mistro 2021‐ITA; Falcaro 2021‐GBR; Kjaer 2021‐DNK; Lei 2020b‐SWE; Palmer 2024‐GBR; Ward 2024‐GBR), one was a case‐control study (Ikeda 2021‐JPN), three were extensions of RCTs (Luostarinen 2018‐FIN; Rana 2013‐FIN; Sankaranarayanan 2018‐IND), one was a cross‐sectional study (Dorton 2015‐USA), and nine were pre‐post vaccine introduction studies (Baldur‐Felskov 2015‐DNK; Goodman 2024‐DEU; Grieger 2024‐DEU; Guo 2023‐USA; Jemal 2013‐USA; Lopez 2018‐ESP; Onuki 2023‐JPN; Rebolj 2022‐GBR; Restivo 2023‐ITA).
From the six cohort studies, one did not report any cases of cervical cancer in the exposed group (Del Mistro 2021‐ITA). A pooled estimate, from five cohort studies that adjusted for confounding, of the impact of HPV vaccination on rates of cervical cancer indicated a reduction of 63% in the long term (RR 0.37, 95% CI 0.25 to 0.56; 5 cohort studies, 4,390,243 females plus 27,946 cases of cervical cancer; I2 = 88%) (Analysis 1.1). The analysis showed high heterogeneity of effect estimates based on age at vaccination. An analysis restricted to those receiving an HPV vaccine at or before the age of 16 years showed a reduction of cervical cancer incidence of 80% (RR 0.20, 95% CI 0.09 to 0.44; 3 cohort studies, 4.54 million person‐years, 15 cases of cervical cancer; I2 = 69%) (Analysis 1.2).
1.1. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 1: Invasive cervical cancer (cohort studies; long‐term)
1.2. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 2: Invasive cervical cancer (cohort studies; long‐term; ≤ 16 years at vaccination)
There was one case‐control study, which did not identify any cases of cervical cancer in the exposed group (Ikeda 2021‐JPN). The study reported a reduced odds of cervical cancer following HPV vaccination (OR 0.22, 95% CI 0.01 to 3.79).
There were three RCT extension studies identified in which no cases of cervical cancer were reported in the exposed groups (Luostarinen 2018‐FIN; Rana 2013‐FIN; Sankaranarayanan 2018‐IND). All three studies reported a reduced incidence of cervical cancer following HPV vaccination, but with wide confidence intervals that incorporated no effect (Analysis 1.3).
1.3. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 3: Invasive cervical cancer (RCT extension studies; medium/long‐term)
One cross‐sectional study was also identified that did not report any cases of cervical cancer in the exposed group (Dorton 2015‐USA).
Nine pre‐post vaccine introduction studies were identified and all reported a reduction in cervical cancer incidence following HPV vaccine introduction (Baldur‐Felskov 2015‐DNK; Goodman 2024‐DEU; Grieger 2024‐DEU; Guo 2023‐USA; Jemal 2013‐USA; Lopez 2018‐ESP; Onuki 2023‐JPN; Rebolj 2022‐GBR; Restivo 2023‐ITA). These studies reported different effect estimates over different time periods, so data were not in a form that allowed for meta‐analysis.
One RCT extension study reported on the effectiveness of two doses and one dose of HPV vaccine, however in both instances no cases of cervical cancer were reported in the exposed groups (Sankaranarayanan 2018‐IND).
Adenocarcinoma in situ
See Table 6 for effect estimates and Table 7 for the risk of bias summary of included studies on adenocarcinoma in situ (AIS). We are unclear about the effect of HPV vaccination on AIS incidence because the certainty of the evidence is very low (very low‐certainty evidence; Table 1).
4. Primary clinical outcomes effect estimates: adenocarcinoma in situ.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Dorton 2015‐USA | Gardasil (Merck quadrivalent) | Female, ≤ 26 years |
Vaccinated: 481 Unvaccinated: 911 |
Risk ratio (long‐term) | 0.06 (0.00 to 1.02) | Unadjusted | Cross‐sectional; no events in exposed group |
| Baldur‐Felskov 2015‐DNK | Gardasil (Merck quadrivalent) | Females, 12 to 99 years* | 5475 cases of adenocarcinoma in situ | Incidence rate ratio (long‐term; 2000 vs 2019) | 1.09 (0.81 to 1.48) | Age‐standardised | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Lopez 2018‐ESP | NR | Female, 11 to 14 years | NR | Incidence rate ratio (long‐term; 2003 vs 2014) | 0.60 (0.58 to 0.62) | Unadjusted | Pre‐ vs post‐vaccine introduction |
NR: not reported
5. Risk of bias summary: adenocarcinoma in situ.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Dorton 2015‐USA | Critical | Serious | Moderate | Low | Moderate | Low | Moderate | Critical |
| Baldur‐Felskov 2015‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Lopez 2018‐ESP | Critical | Low | Serious | Low | Low | Low | Low | Critical |
Three studies were included that reported on AIS following HPV vaccination (Baldur‐Felskov 2015‐DNK; Dorton 2015‐USA; Lopez 2018‐ESP).
One was a cross‐sectional study (Dorton 2015‐USA) and two were pre‐post vaccine introduction studies (Baldur‐Felskov 2015‐DNK; Lopez 2018‐ESP).
The cross‐sectional study reported no cases of AIS in the HPV vaccine group (Dorton 2015‐USA).
One pre‐post vaccine introduction study reported an increase in AIS incidence following HPV vaccine introduction (Baldur‐Felskov 2015‐DNK), while the other reported a reduction (Lopez 2018‐ESP).
Cervical intraepithelial neoplasia grade 3 and above (CIN3+)
See Table 8 for effect estimates and Table 9 for the risk of bias summary of included studies on CIN3+. HPV vaccination probably reduces the incidence of CIN3+ (moderate‐certainty evidence; Table 1).
6. Primary clinical outcomes effect estimates: CIN3+.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Brotherton 2019‐AUS | Gardasil (Merck quadrivalent) | Female, 12 to 15 years | Vaccinated: 174,995 Unvaccinated: 48,845 |
Hazard ratio (3 doses; medium‐term) | 0.43 (0.35 to 0.53) | Age, area of residence, socioeconomic status | Cohort |
| Brotherton 2019‐AUS | Gardasil (Merck quadrivalent) | Female, 12 to 15 years | Vaccinated: 18,190 Unvaccinated: 48,845 |
Hazard ratio (2 doses; medium‐term) | 0.42 (0.27 to 0.64) | Age, area of residence, socioeconomic status | Cohort |
| Brotherton 2019‐AUS | Gardasil (Merck quadrivalent) | Female, 12 to 15 years | Vaccinated: 8618 Unvaccinated: 48,845 |
Hazard ratio (1 dose; medium‐term) | 0.66 (0.41 to 1.06) | Age, area of residence, socioeconomic status | Cohort |
| Castle 2019‐USA | Gardasil (Merck quadrivalent) | Female, < 18 years | Vaccinated: 15,290 Unvaccinated: 60,359 |
Risk ratio (medium‐term) | 0.28 (0.08 to 0.81) | Unadjusted | Cohort |
| Castle 2019‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 20 years | Vaccinated: 15,290 Unvaccinated: 60,359 |
Risk ratio (medium‐term) | 0.85 (0.50 to 1.43) | Unadjusted | Cohort |
| Castle 2019‐USA | Gardasil (Merck quadrivalent) | Female, 21 to 24 years | Vaccinated: 15,290 Unvaccinated: 60,359 |
Risk ratio (medium‐term) | 2.45 (1.73 to 3.48) | Unadjusted | Cohort |
| Del Mistro 2021‐ITA | Gardasil (Merck quadrivalent) | Female, 15 to 25 years | Vaccinated: 4718 Unvaccinated: 91,512 | Risk ratio (long‐term) | 1.11 (0.59 to 2.11) | Unadjusted | Cohort |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 26 years | Vaccinated: 135,758 Unvaccinated: 559,789 | Risk ratio (3 doses; long‐term) | 0.34 (0.29 to 0.40) | Birth year, race | Cohort |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, < 20 years | Vaccinated: 171,156 Unvaccinated: 559,789 | Risk ratio (long‐term) | 0.35 (0.30 to 0.40) | Birth year, race | Cohort |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, ≥ 20 years | Vaccinated: 42,248 Unvaccinated: 559,789 | Risk ratio (long‐term) | 0.64 (0.55 to 0.75) | Birth year, race | Cohort |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, 9‐26 years | Vaccinated: 34,401 Unvaccinated: 559,789 | Risk ratio (2 doses; long‐term) | 0.67 (0.54 to 0.82) | Birth year, race | Cohort |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 26 years | Vaccinated: 43,245 Unvaccinated: 559,789 | Risk ratio (1 dose; long‐term) | 0.60 (0.50 to 0.73) | Birth year, race | Cohort |
| Herweijer 2016‐SWE | Gardasil (Merck quadrivalent) | Female, 11 to 16 years | Vaccinated: 236,372 Unvaccinated: 1,097,319 | Incidence rate ratio (long‐term) | 0.16 (0.08 to 0.32) | Age, parental highest education | Cohort |
| Herweijer 2016‐SWE | Gardasil (Merck quadrivalent) | Female, 17 to 19 years | Vaccinated: 236,372 Unvaccinated: 1,097,319 | Incidence rate ratio (long‐term) | 0.43 (0.33 to 0.57) | Age, parental highest education | Cohort |
| Herweijer 2016‐SWE | Gardasil (Merck quadrivalent) | Female, 20 to 29 years | Vaccinated: 236,372 Unvaccinated: 1,097,319 | Incidence rate ratio (long‐term) | 0.75 (0.59 to 0.95) | Age, parental highest education | Cohort |
| Lehtinen 2017b‐FIN | Cervarix (GSK bivalent) | Female, 16 to 17 years | Vaccinated: 2472 Unvaccinated: 15,665 | Incidence rate ratio (long‐term) | 0.34 (0.12 to 0.92) | Unadjusted | Cohort |
| Lei 2020a‐SWE | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 10 to 16 years | Vaccinated: 25,865 Unvaccinated: 100,400 | Risk ratio (long‐term) | 0.36 (0.31 to 0.42) | Birth cohort | Cohort |
| Lei 2020a‐SWE | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 17 to 22 years | Vaccinated: 26,892 Unvaccinated: 100,400 | Risk ratio (long‐term) | 0.56 (0.50 to 0.64) | Birth cohort | Cohort |
| Orumaa 2024‐NOR | Gardasil (Merck quadrivalent) | Female, 16 to 30 years | Vaccinated: 441 cases Unvaccinated: 14,528 cases |
Incidence rate ratio (long‐term) | 0.37 (0.33 to 0.41) | Age, calendar year | Cohort |
| Orumaa 2024‐NOR | Gardasil (Merck quadrivalent) | Female, < 17 years at vaccination | Vaccinated: 135 cases Unvaccinated: 14,528 cases |
Incidence rate ratio (long‐term) | 0.15 (0.13 to 0.18) | Age, calendar year | Cohort |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 12 to 18+ years | NR | Odds ratio (3 doses; long‐term) | 0.14 (0.08 to 0.25) | Deprivation, rurality | Cohort |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 12 to 18+ years | NR | Odds ratio (2 doses; long‐term) | 0.77 (0.48 to 1.24) | Deprivation, rurality | Cohort |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 12 to 18+ years | NR | Odds ratio (1 dose; long‐term) | 1.19 (0.70 to 2.05) | Deprivation, rurality | Cohort |
| Schurink‐Van't Klooster 2023‐NLD | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 13 to 22 years | Vaccinated: 2233 Unvaccinated: 17,389 |
Odds ratio (2 doses; long‐term) | 0.60 (0.33 to 1.08) | Age, age of vaccination, birth cohort | Cohort |
| Schurink‐Van't Klooster 2023‐NLD | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 13 to 22 years | Vaccinated: 22,549 Unvaccinated: 17,389 |
Odds ratio (3 doses; long‐term) | 0.28 (0.19 to 0.41) | Age, age of vaccination, birth cohort | Cohort |
| Verdoodt 2020‐DNK | Gardasil (Merck quadrivalent) | Female, < 16 years | Vaccinated: 215,309 Unvaccinated: 374,774 | Incidence rate ratio (long‐term) | 0.37 (0.30 to 0.45) | Attained age, socioeconomic position | Cohort |
| Yagi 2019‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 7389 Unvaccinated: 7872 | Risk ratio (long‐term) | 0.07 (0.00 to 1.24) | Unadjusted | Cohort; no events in exposed group |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 26 years | Cases: 2746 Controls: 1247 |
Risk ratio (3 doses; long‐term) | 0.28 (0.21 to 0.36) | Birth year, race | Case‐cohort analysis |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, < 20 years | Cases: 2775 Controls: 1295 |
Risk ratio (long‐term) | 0.27 (0.22 to 0.35) | Birth year, race | Case‐cohort analysis |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, ≥ 20 years | Cases: 2756 Controls: 1074 |
Risk ratio (long‐term) | 0.59 (0.44 to 0.79) | Birth year, race | Case‐cohort analysis |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 26 years | Cases: 2704 Controls: 1053 |
Risk ratio (2 doses; long‐term) | 0.61 (0.42 to 0.90) | Birth year, race | Case‐cohort analysis |
| Gargano 2021‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 26 years | Cases: 2712 Controls: 1064 |
Risk ratio (1 dose; long‐term) | 0.52 (0.37 to 0.75) | Birth year, race | Case‐cohort analysis |
| Ikeda 2021‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Cases: 52 Controls: 12,296 |
Odds ratio (medium‐term) | 0.19 (0.03 to 0.15) | Unadjusted | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 17 years | Cases: 1717 Controls: 8537 |
Incidence rate ratio (long‐term) | 0.45 (0.27 to 0.76) | Matched by age, time since first cytology, years of health plan membership. | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 20 years | Cases: 1751 Controls: 8661 |
Incidence rate ratio (long‐term) | 0.84 (0.59 to 1.21) | Matched by age, time since first cytology, years of health plan membership. | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, ≥ 21 years | Cases: 1771 Controls: 8742 |
Incidence rate ratio (long‐term) | 0.92 (0.59 to 1.17) | Matched by age, time since first cytology, years of health plan membership. | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 21+ years | Cases: 1766 Controls: 8835 |
Incidence rate ratio (3 doses; long‐term) | 0.68 (0.52 to 0.90) | Matched by age, time since first cytology, years of health plan membership. | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 21+ years | Cases: 1742 Controls: 8517 |
Incidence rate ratio (2 doses; long‐term) | 1.02 (0.71 to 1.48) | Matched by age, time since first cytology, years of health plan membership. | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 21+ years | Cases: 1849 Controls: 8588 |
Incidence rate ratio (1 dose; long‐term) | 0.94 (0.68 to 1.30) | Matched by age, time since first cytology, years of health plan membership. | Case‐control |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 1365 Unvaccinated: 1783 | Incidence rate ratio (long‐term) | 0.05 (0.01 to 0.26) | Age‐ and location‐matched | RCT extension |
| Hikari 2022‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 20 to 24 years | Vaccinated: 2467 Unvaccinated: 4786 | Risk ratio (long‐term) | 0.22 (0.01 to 4.00) | Unadjusted | Cross‐sectional; no events in exposed group |
| Ozawa 2017‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 1002 Unvaccinated: 4922 | Risk ratio (long‐term) | 0.14 (0.02 to 1.05) | Unadjusted | Cross‐sectional; no events in exposed group |
| Shiko 2020‐JPN | Cervarix (GSK bivalent) | Female, 12 to 16 years | Vaccinated: 3770 Unvaccinated: 30,511 | Risk ratio (medium‐term) | 0.09 (0.00 to 0.42) | Age, place of screening | Cross‐sectional; no events in exposed group |
| Tozawa‐Ono 2021‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 3102 Unvaccinated: 8611 | Risk ratio (medium‐term) | 0.59 (0.17 to 2.07) | Unadjusted | Cross‐sectional |
| Wright 2019‐USA | Gardasil (Merck quadrivalent) | Female, 11 to 26 years | Vaccinated: 2977 Unvaccinated: 11,176 | Odds ratio (medium‐term) | 1.00 (0.60 to 1.70) | Age | Cross‐sectional |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years | 6021 cases total | Average annual percent change (2008 to 2016) | ‐10.4% (‐13.1% to ‐7.5%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years | 6021 cases total | Average annual percent change (2008 to 2016) | 0.7% (‐2.1% to 3.7%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 34 years | 6021 cases total | Average annual percent change (2008 to 2016) | 7.1% (3.8% to 10.6%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 35 to 39 years | 6021 cases total | Average annual percent change (2008 to 2016) | 3.5% (‐2.1% to 9.3%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years | 6021 cases total | Incidence rate (2008‐2009 vs 2015‐2016) | 0.45 (0.32 to 0.60) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years | 6021 cases total | Incidence rate (2008‐2009 vs 2015‐2016) | 1.01 (0.85 to 1.18) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 34 years | 6021 cases total | Incidence rate (2008‐2009 vs 2015‐2016) | 1.58 (1.32 to 1.88) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 35 to 39 years | 6021 cases total | Incidence rate (2008‐2009 vs 2015‐2016) | 1.48 (1.15 to 1.88) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Rebolj 2022‐GBR | Cervarix (GSK bivalent) | Female, 24 to 25 years | N = 64,274 | Vaccine effectiveness (long‐term) | 79% (73% to 83%) | Deprivation and laboratory | Pre‐ vs post‐vaccine introduction |
| Thamsborg 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 15 years | Pre‐vaccine: 19,629 Post‐vaccine: 26,215 |
Incidence rate ratio (long‐term; 1999‐2008 vs 2009‐2018) | 0.68 (0.58 to 0.79) | Unadjusted | Pre‐ vs post‐vaccine introduction |
CIN3+: cervical intraepithelial neoplasia grade 3 or higher; NR: not reported; RCT: randomised controlled trial
7. Risk of bias summary: CIN3+.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Brotherton 2019‐AUS | Serious | Serious | Low | Low | Moderate | Low | Moderate | Serious |
| Castle 2019‐USA | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Del Mistro 2021‐ITA | Critical | Low | Moderate | Low | Low | Low | Low | Critical |
| Gargano 2021‐USA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Herweijer 2016‐SWE | Serious | Low | Moderate | Low | Low | Low | Low | Serious |
| Lehtinen 2017b‐FIN | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Lei 2020a‐SWE | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Orumaa 2024‐NOR | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Palmer 2019‐GBR | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Schurink‐Van't Klooster 2023‐NLD | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Verdoodt 2020‐DNK | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Yagi 2019‐JPN | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Ikeda 2021‐JPN | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Silverberg 2018‐USA | Serious | Serious | Low | Low | Low | Low | Low | Serious |
| Kreimer 2011‐CRI | Moderate | Moderate | Moderate | Low | Moderate | Low | Low | Moderate |
| Hikari 2022‐JPN | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Ozawa 2017‐JPN | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Shiko 2020‐JPN | Serious | Moderate | Moderate | Low | Moderate | Low | Low | Serious |
| Tozawa‐Ono 2021‐JPN | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Wright 2019‐USA | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Gargano 2023‐USA | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Rebolj 2022‐GBR | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Thamsborg 2020‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
CIN3+: cervical intraepithelial neoplasia grade 3 or higher
Twenty‐three studies were included that reported on CIN3+ following HPV vaccination (Brotherton 2019‐AUS; Castle 2019‐USA; Del Mistro 2021‐ITA; Gargano 2021‐USA; Gargano 2023‐USA; Herweijer 2016‐SWE; Hikari 2022‐JPN; Ikeda 2021‐JPN; Kreimer 2011‐CRI; Lehtinen 2017b‐FIN; Lei 2020a‐SWE; Orumaa 2024‐NOR; Ozawa 2017‐JPN; Palmer 2019‐GBR; Rebolj 2022‐GBR; Schurink‐Van't Klooster 2023‐NLD; Shiko 2020‐JPN; Silverberg 2018‐USA; Thamsborg 2020‐DNK; Tozawa‐Ono 2021‐JPN; Verdoodt 2020‐DNK; Wright 2019‐USA; Yagi 2019‐JPN).
Eleven were cohort studies (Brotherton 2019‐AUS; Castle 2019‐USA; Del Mistro 2021‐ITA; Herweijer 2016‐SWE; Lehtinen 2017b‐FIN; Lei 2020a‐SWE; Orumaa 2024‐NOR; Palmer 2019‐GBR; Schurink‐Van't Klooster 2023‐NLD; Verdoodt 2020‐DNK; Yagi 2019‐JPN), two were case‐control studies (Ikeda 2021‐JPN; Silverberg 2018‐USA), one was an RCT extension study (Kreimer 2011‐CRI), five were cross‐sectional studies (Hikari 2022‐JPN; Ozawa 2017‐JPN; Shiko 2020‐JPN; Tozawa‐Ono 2021‐JPN; Wright 2019‐USA), and three were pre‐post vaccine introduction studies (Gargano 2023‐USA; Rebolj 2022‐GBR; Thamsborg 2020‐DNK). One study reported both a cohort analysis as well as a case‐cohort analysis (Gargano 2021‐USA).
From the cohort studies, four did not adjust for confounding, with one not reporting any cases of CIN3+ in the exposed group (Yagi 2019‐JPN). A pooled estimate from cohort studies, adjusted for confounding, of the impact of HPV vaccination on rates of CIN3+ indicated a reduction of 57% in the medium term (RR 0.43, 95% CI 0.35 to 0.53; 1 cohort study, 223,840 females) and 61% in the long term (RR 0.39, 95% CI 0.32 to 0.48; 7 cohort studies, > 3.4 million females; I2 = 91%) (Analysis 1.4). An analysis restricted to those receiving an HPV vaccine at or before the age of 16 years showed a reduction of CIN3+ incidence of 74% in the long term (RR 0.26, 95% CI 0.12 to 0.56; 2 cohort studies, 1.5 million females; I2 = 80%) (Analysis 1.5).
1.4. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 4: CIN3+ (cohort studies; medium/long‐term)
1.5. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 5: CIN3+ (cohort studies; medium/long‐term; ≤ 16 years at vaccination)
The two case‐control studies (Ikeda 2021‐JPN; Silverberg 2018‐USA) and the case‐cohort analysis (Gargano 2021‐USA) each reported a reduced odds of CIN3+ following HPV vaccination (Table 8).
The RCT extension study reported a reduced incidence of CIN3+ following HPV vaccination (incidence rate ratio (IRR) 0.05, 95% CI 0.01 to 0.26; 3148 females) (Kreimer 2011‐CRI).
Of the five cross‐sectional studies, four reported a reduction in CIN3+ following HPV vaccination (Hikari 2022‐JPN; Ozawa 2017‐JPN; Shiko 2020‐JPN; Tozawa‐Ono 2021‐JPN) and one reported no difference (Wright 2019‐USA) (Table 8).
The three pre‐post vaccine introduction studies reported a decreased incidence of CIN3+ when comparing time periods before and after HPV vaccine was introduced (Gargano 2023‐USA; Rebolj 2022‐GBR; Thamsborg 2020‐DNK) (Table 8).
Four studies reported on the effectiveness of two doses or one dose of HPV vaccine (Brotherton 2019‐AUS; Gargano 2021‐USA; Palmer 2019‐GBR; Silverberg 2018‐USA). Two of the three cohort studies reported a reduction of CIN3+ following two doses of HPV vaccine (Brotherton 2019‐AUS; Gargano 2021‐USA) and one cohort study reported a reduction of CIN3+ following one dose (Gargano 2021‐USA). One case‐control study reported no reduction of CIN3+ from one or two doses of HPV vaccine (Silverberg 2018‐USA).
Vaginal cancer
See Table 10 for effect estimates and Table 11 for the risk of bias summary of included studies on vaginal cancer. HPV vaccination may reduce vaginal cancer incidence (low‐certainty evidence; Table 12).
8. Primary clinical outcomes effect estimates: vaginal cancer.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Bertoli 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 27 years | 721 cases of vaginal squamous cell carcinoma | Incidence rate ratio (long‐term; 1978‐82 vs 2013‐17) | 0.60 (0.09 to 3.08) | Age‐standardised | Pre‐ vs post‐vaccine introduction |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Female, age NR | NR | Annual percent change (long‐term; 2000 vs 2009) | White: ‐1.4% Black: ‐4.1% Asian/Pacific Islander: ‐2.1% American Indian/Alaska native: NR Hispanic: ‐0.6% |
Age | Pre‐ vs post‐vaccine introduction; data only reported by ethnic groups |
| Guo 2023‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 34 years at outcome | 160 cases of vaginal squamous cell carcinoma | Rate ratio (long‐term; 2002‐6 vs 2015‐19) | 0.65 (0.47 to 0.90) | Age‐standardised | Pre‐ vs post‐vaccine introduction |
NR: not reported
9. Risk of bias summary: vaginal cancer.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Bertoli 2020‐DNK | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
| Jemal 2013‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Guo 2023‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
10. Summary of findings – additional clinical outcomes.
|
Population: general population of any age Setting: any setting Intervention: full or partial series HPV vaccination Comparator: no vaccination | ||||
| Outcome | Number of studies (participants) | Summary of effect | Overall certainty of the evidence | Interpretation of findings |
| Invasive vaginal cancer | Three pre‐post vaccine introduction studies (> 881 cases of vaginal cancer) | Three pre‐post vaccine introduction studies reported a reduction in vaginal cancer incidence between the pre‐ and post‐introduction periods. | LOWa,b
⊕⊕◯◯ Downgraded due to methodological limitations and imprecision. |
HPV vaccination may reduce vaginal cancer incidence. |
| Invasive anal cancer | Three pre‐post vaccine introduction studies (> 42,127 cases) | In females and males, two pre‐post vaccine introduction studies reported a decrease in anal cancer incidence between the pre‐ and post‐introduction periods and one study reported an increase. | VERY LOWa,b,c
⊕◯◯◯ Downgraded due to methodological limitations, inconsistency and imprecision. |
We do not know about the effect of HPV vaccine on anal cancer incidence because the certainty of the evidence is very low. |
| Invasive penile cancer | Two pre‐post vaccine introduction studies (> 15,804 cases) | Two pre‐post vaccine introduction studies reported a decrease in penile cancer incidence between the pre‐ and post‐introduction periods. | LOWb,d
⊕⊕◯◯ Downgraded due to methodological limitations and imprecision. |
HPV vaccination may reduce penile cancer incidence. |
| Invasive head and neck cancer | One cohort study (1,305,954 males and females) One RCT extension study (189,901 person‐years) Three pre‐post vaccine introduction studies (284,372 males and females plus 234,931 cases of oropharyngeal cancer) |
In females and males, one cohort study reported a decreased risk of head and neck cancer following HPV vaccination. The RCT extension study did not identify any cases of head and neck cancer in vaccinated participants. Two pre‐post vaccine introduction studies reported a reduction in head and neck cancer incidence between the pre‐ and post‐introduction periods. One pre‐post vaccine introduction study reported inconsistent results, with some ethnic groups seeing an increased incidence and others a decrease. |
LOWb,e
⊕⊕◯◯ Downgraded due to methodological limitations and imprecision. |
HPV vaccination may reduce head and neck cancer incidence. |
| Cervical intraepithelial neoplasia grade 3 (CIN3) | Three cohort studies (> 214,800,000 person‐years; 27,946 cases of cervical cancer) One case‐control study (12,340 females) One RCT extension (66,340 females) Three cross‐sectional studies (12,923 females) Five pre‐post vaccine introduction studies (234,775 females plus 73,576 cases of CIN3) |
One cohort study reported a reduced risk of CIN3 following HPV vaccination (RR 0.17, 95% CI 0.06 to 0.45). Two other cohort studies reported no cases of CIN3 in the vaccinated participants. The case‐control study reported a reduced odds of CIN3 in vaccinated participants. The RCT extension study reported no cases of CIN3 in the vaccinated participants. Two cross‐sectional studies reported no difference in the risk of CIN3 in vaccinated and unvaccinated participants. One cross‐sectional study reported no cases of CIN3 in the vaccinated participants. Four pre‐post vaccine introduction studies reported a reduction in CIN3 incidence between the pre‐ and post‐introduction periods and one study reported an increased risk. |
MODERATEg
⊕⊕⊕◯ Downgraded due to methodological limitations |
HPV vaccination probably reduces the incidence of CIN3. |
| Cervical intraepithelial neoplasia grade 2 (CIN2) | Four cohort studies (> 50,064 females) One case‐control study (12,461 females) Two cross‐sectional studies (12,074 females) Four pre‐post vaccine introduction studies (109,070 females plus 4296 cases of CIN2) |
Three cohort studies reported a reduced risk of CIN2 following HPV vaccination. One other cohort study reported no difference in the risk of CIN2 between vaccinated and unvaccinated participants. One case‐control study reported reduced odds of CIN2 in vaccinated participants. Two cross‐sectional studies reported no difference in risk of CIN2 between vaccinated and unvaccinated participants. Three pre‐post vaccine introduction studies reported a reduction in CIN2 incidence between the pre‐ and post‐introduction periods and one study reported no difference. |
MODERATEh
⊕⊕⊕◯ Downgraded due to methodological limitations. |
HPV vaccination probably reduces the incidence of CIN2. |
| High‐grade vaginal intraepithelial neoplasia (VaIN) | One pre‐post vaccine introduction study (945 cases of VaIN) | One pre‐post vaccine introduction study reported a reduction in VaIN incidence between the pre‐ and post‐introduction periods. | LOWi,j
⊕⊕◯◯ Downgraded due to methodological limitations and imprecision. |
HPV vaccination may reduce the incidence of VaIN. |
| High‐grade vulval intraepithelial neoplasia (VIN) | Two pre‐post vaccine introduction studies (6128 cases of VIN) | One pre‐post vaccine introduction study reported a reduction in VIN incidence between the pre‐ and post‐introduction periods and the other reported an increase in VIN incidence. | VERY LOWc,j,k
⊕◯◯◯ Downgraded due to methodological limitations, inconsistency and imprecision. |
We do not know about the effect of HPV vaccine on VIN incidence because the certainty of the evidence is very low. |
| High‐grade anal intraepithelial neoplasia (AIN) | One cohort study (30 cases of AIN) One pre‐post vaccine introduction study (2616 cases of AIN) |
One cohort study reported a reduced risk of AIN following HPV vaccination. One pre‐post vaccine introduction study reported an increase in AIN incidence in males and females between the pre‐ and post‐introduction periods. |
LOWc,l
⊕⊕◯◯ Downgraded due to methodological limitations and inconsistency. |
HPV vaccination may reduce the incidence of AIN. |
| High‐grade penile intraepithelial neoplasia (PeIN) | No studies were identified that reported on this outcome. | |||
AGW: anogenital warts; AIN: anal intraepithelial neoplasia (precancer of the perianal skin); AIS: adenocarcinoma in situ (precancer of the glandular cells of the cervix, also known as cervical intraepithelial glandular neoplasia (CGIN)); CI: confidence interval; CIN: cervical intraepithelial neoplasia (precancer of the squamous (skin‐like) cells of cervix); CIN3+: cervical intraepithelial neoplasia grade 3 or higher; CIN2: cervical intraepithelial neoplasia grade 2; CIN2+: cervical intraepithelial neoplasia grade 2 or higher; CIN3: cervical intraepithelial neoplasia grade 3; HPV: human papillomavirus; PeIN: penile intraepithelial neoplasia (precancer of the penile skin); RCT: randomised controlled trial; RR: risk ratio; VaIN: vaginal intraepithelial neoplasia (precancer of the vaginal skin/mucosa); VIN: vulval intraepithelial neoplasia (precancer of the vulval skin)
aAll three pre‐post vaccine introduction studies were at serious risk of bias. The main concerns for bias were the potential for residual confounding and classification of the intervention. Overall, we have downgraded one level for methodological limitations.
bDowngraded one level for imprecision – one study with a confidence interval around the effect estimate that incorporates benefit, no effect and harm. One other study did not report the number of cases or an overall effect estimate.
cDowngraded one level for inconsistency – studies show no effect, a possible harm and a possible benefit of HPV vaccination.
dOne pre‐post vaccine introduction study at serious risk of bias and one at critical risk of bias. The main concerns for bias were the potential for residual confounding and classification of the intervention. Overall, we have downgraded one level for methodological limitations.
eOne cohort study at critical risk of bias, one RCT extension study at serious risk of bias, and three pre‐post vaccine introduction studies at serious or critical risk of bias. Overall, we have downgraded one level for methodological limitations.
fOne cohort study at moderate risk of bias, two cohorts at critical risk. The other designs were at serious or critical risk of bias. Overall, we have downgraded one level for methodological limitations.
hTwo cohort studies at serious risk of bias and two critical at risk. The other designs were at critical risk of bias. Overall, we have downgraded one level for methodological limitations.
iOne pre‐post vaccine introduction study at serious risk of bias. Overall, we have downgraded one level for methodological limitations.
jDowngraded one level for imprecision – one study with confidence intervals around the effect estimates that incorporate benefit, no effect and harm.
kTwo pre‐post vaccine introduction studies, one at serious risk of bias and one at critical risk. Overall, we have downgraded one level for methodological limitations.
lOne cohort study at serious risk of bias and one pre‐post vaccine introduction study at serious risk of bias. Overall, we have downgraded one level for methodological limitations.
Three studies were included that reported on vaginal cancer following HPV vaccination (Bertoli 2020‐DNK; Guo 2023‐USA; Jemal 2013‐USA). All three were pre‐post vaccine introduction studies.
One study reported a decrease in vaginal cancer incidence from 1978‐1982 to 2013‐2017 but with confidence intervals that included no difference (Bertoli 2020‐DNK). The second study reported a decrease in vaginal cancer incidence from 2002‐2006 to 2015‐2019 (Guo 2023‐USA). The third study reported decreased incidence of vaginal cancer across all ethnic groups evaluated (Jemal 2013‐USA) (Table 10).
Vulval cancer
See Table 13 for effect estimates and Table 14 for the risk of bias summary of included studies on vulval cancer. We do not know about the effect of HPV vaccine on vulval cancer incidence because the certainty of the evidence is very low (very low‐certainty evidence; Table 1).
11. Primary clinical outcomes effect estimates: vulval cancer.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Luostarinen 2018‐FIN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 14 to 17 years | N = 189,901 person‐years | Incidence rate ratio (long‐term) | 0.00 (0.00 to 73.81) | Unadjusted | RCT extension; no events in exposed group |
| Guo 2023‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 24 years at outcome | 374 cases of vulvar squamous cell carcinoma | Rate ratio (long‐term; 2002‐6 vs 2015‐19) | 0.18 (0.13 to 0.24) | Age‐standardised | Pre‐ vs post‐vaccine introduction |
| Guo 2023‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 34 years at outcome | 1679 cases of vulvar squamous cell carcinoma | Rate ratio (long‐term; 2002‐6 vs 2015‐19) | 0.54 (0.48 to 0.59) | Age‐standardised | Pre‐ vs post‐vaccine introduction |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Female, age NR | NR | Annual percent change (long‐term, 2000 vs 2009) | White: 1.4% Black: 0.9% Asian/Pacific Islander: ‐1.3% American Indian/Alaska native: NR Hispanic: ‐0.6% |
Age | Pre‐ vs post‐vaccine introduction; data only reported by ethnic groups |
| Rasmussen 2020‐DNK | NR | Female, 12 to 26 years | NR | Annual percentage change (long‐term; 1997‐1998 vs 2017‐2018) | 2.94% (2.25% to 3.63%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Restivo 2023‐ITA | NR | Female, age NR | N = 34,510 cases | Rate ratio (2008 vs 2018) | 0.87 (0.64 to 1.19) | Unadjusted | Pre‐ vs post‐vaccine introduction |
NR: not reported
12. Risk of bias summary: vulval cancer.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Luostarinen 2018‐FIN | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Guo 2023‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Jemal 2013‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Rasmussen 2020‐DNK | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
| Restivo 2023‐ITA | Serious | Serious | Serious | Low | Low | Low | Low | Serious |
Five studies were included that reported on vulval cancer following HPV vaccination (Guo 2023‐USA; Jemal 2013‐USA; Luostarinen 2018‐FIN; Rasmussen 2020‐DNK; Restivo 2023‐ITA).
One study was an RCT extension study with no vulval cancer events reported in the HPV vaccine‐exposed group (Luostarinen 2018‐FIN). The other four were pre‐post vaccine introduction studies (Guo 2023‐USA; Jemal 2013‐USA; Rasmussen 2020‐DNK; Restivo 2023‐ITA). One study reported an increase in vulval cancer incidence (Rasmussen 2020‐DNK) and two studies reported a decrease when comparing time periods before and after HPV vaccine introduction (Guo 2023‐USA; Restivo 2023‐ITA). The other study reported inconsistent results, with some ethnic groups seeing an increased incidence and others a decrease (Jemal 2013‐USA) (Table 13).
Anal cancer
See Table 15 for effect estimates and Table 16 for the risk of bias summary of included studies on anal cancer. We do not know about the effect of HPV vaccine on anal cancer incidence because the certainty of the evidence is very low (very low‐certainty evidence; Table 12).
13. Primary clinical outcomes effect estimates: anal cancer.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Guo 2023‐USA | NR | Male and female, 20 to 44 years | N = 8062 | Rate ratio (2001‐2008 vs 2009‐2018) | 0.76 (0.7 to 0.83) | Age adjusted to US population | Pre‐ vs post‐vaccine introduction |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Female, age NR | NR | Annual percent change (long term; 2000 vs 2009) | White: 3.7% Black: 2.5% Asian/Pacific Islander: 1.6% American Indian/Alaska native: NR Hispanic: 0.7% |
Age | Pre‐ vs post‐vaccine introduction; data only reported by ethnic groups |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Male, age NR | NR | Annual percent change (long term; 2000 vs 2009) | White: 2.6% Black: 5.6% Asian/Pacific Islander: 2.1% American Indian/Alaska native: NR Hispanic: 0.9% |
Age | Pre‐ vs post‐vaccine introduction; data only reported by ethnic groups |
| Restivo 2023‐ITA | NR | Male, age NR | N = 42,127 cases | Rate ratio (2008 vs 2018) | 0.83 (0.58 to 1.19) | Unadjusted | Pre‐ vs post‐vaccine introduction |
NR: not reported
14. Risk of bias summary: anal cancer.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Guo 2023‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Jemal 2013‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Restivo 2023‐ITA | Serious | Serious | Serious | Low | Low | Low | Low | Serious |
Three studies were included that reported on anal cancer following HPV vaccination (Guo 2023‐USA; Jemal 2013‐USA; Restivo 2023‐ITA). All three were pre‐post vaccine introduction studies.
One study reported an increased incidence of anal cancer in both males and females between 2000 and 2009 (Jemal 2013‐USA), while the other two studies reported a decrease (Guo 2023‐USA; Restivo 2023‐ITA) (Table 15).
Penile cancer
See Table 17 for effect estimates and Table 18 for the risk of bias summary of included studies on penile cancer. HPV vaccination may reduce penile cancer incidence (low‐certainty evidence; Table 12).
15. Primary clinical outcomes effect estimates: penile cancer.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Male, age NR | NR | Annual percent change (long‐term; 2000 vs 2009) | White: ‐0.7% Black: ‐1.1% Asian/Pacific Islander: 0.5% American Indian/Alaska native: NR Hispanic: ‐0.4% |
Age | Pre‐ vs post‐vaccine introduction; data only reported by ethnic groups |
| Restivo 2023‐ITA | NR | Male, age NR | N = 15,804 cases | Rate ratio (2008 vs 2018) | 0.96 (0.54 to 1.71) | Unadjusted | Pre‐ vs post‐vaccine introduction |
NR: not reported
16. Risk of bias summary: penile cancer.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Jemal 2013‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Restivo 2023‐ITA | Critical | Serious | Serious | Low | Low | Low | Low | Critical |
Two studies were included that reported on penile cancer following HPV vaccination (Jemal 2013‐USA; Restivo 2023‐ITA). Both were pre‐post vaccine introduction studies and reported decreased incidence of penile cancer in males (Table 17).
Head and neck cancer
See Table 19 for effect estimates and Table 20 for the risk of bias summary of included studies on head and neck cancer. HPV vaccination may reduce head and neck cancer incidence (low‐certainty evidence; Table 12).
17. Primary clinical outcomes effect estimates: head and neck cancer.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Katz 2021‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 45 to 64 years* | Vaccinated: 14,078 Unvaccinated: 687,567 |
Risk ratio (long‐term) | 0.11 (0.03 to 0.33) | Unadjusted | Cohort; *age at outcome |
| Katz 2021‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Male, 45 to 64 years* | Vaccinated: 4720 Unvaccinated: 599,589 |
Risk ratio (long‐term) | 0.04 (0.01 to 0.30) | Unadjusted | Cohort; *age at outcome |
| Luostarinen 2018‐FIN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 14 to 17 years | N = 189,901 person‐years | Incidence rate ratio (long‐term) | 0.00 (0.00 to 73.81) | Unadjusted | RCT extension; no events in exposed group |
| Guo 2023‐USA | NR | Female 25 to 34 years | 279 cases of oropharyngeal squamous cell carcinoma | Rate ratio (2002‐2006 vs 2015‐2019) | 0.87 (0.68 to 1.11) | Age‐adjusted to US population | Pre‐ vs post‐vaccine introduction |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Female, age NR | NR | Annual percent change (long‐term; 2000 vs 2009) | White: 1.7% Black: ‐0.3% Asian/Pacific Islander: ‐2.5% American Indian/Alaska native: NR Hispanic: 0.2% |
Age | Pre‐ vs post‐vaccine introduction; data only reported by ethnic groups |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Male, age NR | NR | Annual percent change (long‐term; 2000 vs 2009) | White: 3.9% Black: ‐1.6% Asian/Pacific Islander: 1.0% American Indian/Alaska native: 4.9% Hispanic: 0.8% |
Age | Pre‐ vs post‐vaccine introduction; data only reported by ethnic groups |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Female, age NR | N = 55,108 | Rate ratio (2014‐2018 vs 2002‐2006) | 0.89 (0.84 to 0.93) | Age‐adjusted to the 2000 US standard population | Pre‐ vs post‐vaccine introduction |
| Jemal 2013‐USA | Gardasil (Merck quadrivalent) | Male, age NR | N = 229,264 | Rate ratio (2014‐2018 vs 2002‐2006) | 0.86 (0.78 to 0.95) | Age‐adjusted to the 2000 US standard population | Pre‐ vs post‐vaccine introduction |
| Restivo 2023‐ITA | NR | Female and male, age NR | N = 234,652 cases (oropharyngeal cancer) | Rate ratio (2008 vs 2018) | 0.69 (0.52 to 0.92) | Unadjusted | Pre‐ vs post‐vaccine introduction |
NR: not reported; RCT: randomised controlled trial
18. Risk of bias summary: head and neck cancer.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Katz 2021‐USA | Critical | Serious | Low | Low | Serious | Low | Serious | Critical |
| Luostarinen 2018‐FIN | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Guo 2023‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Jemal 2013‐USA | Serious | Moderate | Serious | Low | Low | Low | Moderate | Serious |
| Restivo 2023‐ITA | Critical | Serious | Serious | Low | Low | Low | Low | Critical |
Five studies were included that reported on head and neck cancer following HPV vaccination (Guo 2023‐USA; Jemal 2013‐USA; Katz 2021‐USA; Luostarinen 2018‐FIN; Restivo 2023‐ITA).
One was a cohort study and reported a reduced risk of head and neck cancer in both females (RR 0.11, 95% CI 0.03 to 0.33) and males (RR 0.04, 95% CI 0.01 to 0.30) (Katz 2021‐USA).
One study was an RCT extension study with no head and neck cancer events reported in the HPV vaccine‐exposed group (Luostarinen 2018‐FIN).
Three studies were pre‐post vaccine introduction studies (Guo 2023‐USA; Jemal 2013‐USA; Restivo 2023‐ITA), two of which reported decreased incidence of head and neck cancer in males and females (Guo 2023‐USA; Restivo 2023‐ITA) (Table 19). One study reported inconsistent results, with some ethnic groups seeing an increased incidence and others a decrease (Jemal 2013‐USA).
Cervical intraepithelial neoplasia grade 3 (CIN3)
See Table 21 for effect estimates and Table 22 for the risk of bias summary of included studies on CIN3. HPV vaccination probably reduces the incidence of CIN3 (moderate‐certainty evidence; Table 12).
19. Primary clinical outcomes effect estimates: CIN3.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Falcaro 2021‐GBR | Gardasil (Merck quadrivalent) | Female 12 to 13 years | 214,800,000 person‐years; 27,946 cases of cervical cancer |
Incidence rate ratio (long‐term) | 0.03 (0.02 to 0.04) | Age, cohort, age‐by‐cohort interactions, linear trend (drift), dummy variables for the Jade Goody effect (publicity surrounding the last months and death of the celebrity Jade Goody from cervical cancer), seasonal effects, screening awareness campaign | Cohort |
| Falcaro 2021‐GBR | Gardasil (Merck quadrivalent) | Female 14 to 16 years | 214,800,000 person‐years; 27,946 cases of cervical cancer |
Incidence rate ratio (long‐term) | 0.25 (0.23 to 0.28) | Age, cohort, age‐by‐cohort interactions, linear trend (drift), dummy variables for the Jade Goody effect (publicity surrounding the last months and death of the celebrity Jade Goody from cervical cancer), seasonal effects, screening awareness campaign | Cohort |
| Falcaro 2021‐GBR | Gardasil (Merck quadrivalent) | Female 16 to 18 years | 214,800,000 person‐years; 27,946 cases of cervical cancer |
Incidence rate ratio (long‐term) | 0.61 (0.59 to 0.64) | Age, cohort, age‐by‐cohort interactions, linear trend (drift), dummy variables for the Jade Goody effect (publicity surrounding the last months and death of the celebrity Jade Goody from cervical cancer), seasonal effects, screening awareness campaign | Cohort |
| Paraskevaidis 2020‐GRC | NR | Female, NR | Vaccinated: 849 Unvaccinated: 849 |
Risk ratio (long‐term) | 0.01 (0.00 to 0.23) | Unadjusted | Cohort; no events in exposed group |
| Yagi 2019‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 7389 Unvaccinated: 7872 | Risk ratio (long‐term) | 0.07 (0.00 to 1.24) | Unadjusted | Cohort; no events in exposed group |
| Ikeda 2021‐JPN | Cervarix (GSK bivalent; Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Cases: 44 Controls: 12,296 |
Odds ratio (medium‐term) | 0.27 (0.08 to 0.89) | Unadjusted | Case‐control |
| Rana 2013‐FIN | Gardasil (Merck quadrivalent) | Female, 16 to 17 years | Vaccinated: 3464 Unvaccinated: 62,876 |
Risk ratio (long‐term) | 0.15 (0.01 to 2.47) | Unadjusted | RCT extension: no events in exposed group |
| Hiramatsu 2021‐JPN | Cervarix (GSK bivalent; Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Vaccinated: 170 Unvaccinated: 877 |
Risk ratio (medium‐term) | 5.13 (0.10 to 257.90) | Unadjusted | Cross‐sectional; no events in exposed or unexposed groups |
| Munro 2017‐GBR | Cervarix (GSK bivalent; Gardasil (Merck quadrivalent) | Female, 20 to 25 years* | Vaccinated: 67 Unvaccinated: 96 |
Risk ratio (long‐term) | 0.37 (0.12 to 1.18) | Unadjusted | Cross‐sectional; *age at outcome |
| Tozawa‐Ono 2021‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 3102 Unvaccinated: 8611 | Risk ratio (medium‐term) | 0.59 (0.17 to 2.07) | Unadjusted | Cross‐sectional |
| Baldur‐Felskov 2015‐DNK | Gardasil (Merck quadrivalent) | Females, 12 to 99 years* | 70,753 cases | Incidence rate ratio (long‐term; 2000 vs 2019) | 1.10 (1.02 to 1.19) | Age‐standardised | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Benard 2017‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 19 years* | 135 cases | Annual percent change (long‐term; 2007‐2020) | ‐34.0% (‐55.0 to ‐2.9) | Changes in cervical screening | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Benard 2017‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | 1187 cases | Annual percent change (long‐term; 2007‐2020) | ‐5.8% (‐9.1 to ‐2.4) | Changes in cervical screening | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Benard 2017‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years* | 1501 cases | Annual percent change (long‐term; 2007‐2020) | 5.2% (2.8 to 7.7) | Changes in cervical screening | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Cuschieri 2023‐GBR | Cervarix (GSK bivalent) | Female, 20 to 25 years* | Pre‐vaccine: 397 Post‐vaccine: 1309 |
Odds ratio (long‐term; 2011 vs 2017) | 0.34 (0.23 to 0.52) | Diagnosis year, year of birth, deprivation quintile | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Donken 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 9 to 14 years | Pre‐vaccine: 125,342 Post‐vaccine: 46,207 |
Incidence rate ratio (long‐term; 2004‐8 vs 2009‐17) | 0.26 (0.16 to 0.42) | Birth year and age at first screening | Pre‐ vs post‐vaccine introduction |
| Goodman 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 28 to 33 years | Pre‐vaccine: 22,533 Post‐vaccine: 38,987 |
Relative risk (long‐term; 2013 vs 2021) | 0.44 (0.26 to 0.75) | Unadjusted | Pre‐ vs post‐vaccine introduction |
CIN3: cervical intraepithelial neoplasia grade 3; NR: not reported; RCT: randomised controlled trial
20. Risk of bias summary: CIN3.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Falcaro 2021‐GBR | Moderate | Low | Low | Low | Low | Low | Low | Moderate |
| Paraskevaidis 2020‐GRC | Critical | Serious | Serious | Low | Serious | Low | Moderate | Critical |
| Yagi 2019‐JPN | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Ikeda 2021‐JPN | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Rana 2013‐FIN | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Hiramatsu 2021‐JPN | Critical | Serious | Low | Low | Moderate | Low | Low | Critical |
| Munro 2017‐GBR | Critical | Low | Low | Low | Serious | Low | Low | Critical |
| Tozawa‐Ono 2021‐JPN | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Baldur‐Felskov 2015‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Benard 2017‐USA | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
| Cuschieri 2023‐GBR | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Donken 2021‐CAN | Serious | Low | Serious | Low | Moderate | Low | Low | Serious |
| Goodman 2024‐DEU | Critical | Low | Serious | Low | Low | Low | Low | Critical |
CIN3: cervical intraepithelial neoplasia grade 3
Thirteen studies were included that reported on CIN3 following HPV vaccination (Baldur‐Felskov 2015‐DNK; Benard 2017‐USA; Cuschieri 2023‐GBR; Donken 2021‐CAN; Falcaro 2021‐GBR; Goodman 2024‐DEU; Hiramatsu 2021‐JPN; Ikeda 2021‐JPN; Munro 2017‐GBR; Paraskevaidis 2020‐GRC; Rana 2013‐FIN; Tozawa‐Ono 2021‐JPN; Yagi 2019‐JPN).
Three studies were cohort studies (Falcaro 2021‐GBR; Paraskevaidis 2020‐GRC; Yagi 2019‐JPN), two of which reported no cases of CIN3 in the HPV vaccine‐exposed groups (Paraskevaidis 2020‐GRC; Yagi 2019‐JPN). The other cohort study reported a large decrease in CIN3 incidence following HPV vaccine (RR 0.17, 95% CI 0.06 to 0.45; 1 cohort study, 214.8 million person‐years; I2 = 100%) (Analysis 1.6) (Falcaro 2021‐GBR). This decrease was greater when limited to those receiving the HPV vaccine at or before age 16 years (RR 0.09, 95% CI 0.01 to 0.70; 1 cohort study, 214.8 million person‐years; I2 = 99%) (Analysis 1.7).
1.6. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 6: CIN3 (cohort studies; long‐term)
1.7. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 7: CIN3 (cohort studies; long‐term; ≤ 16 years at vaccination)
One case‐control study reported a reduced odds of CIN3 following HPV vaccination (OR 0.27, 95% CI 0.08 to 0.89) (Ikeda 2021‐JPN).
One RCT extension study reported no CIN3 events in the HPV vaccine‐exposed group (Rana 2013‐FIN).
Three studies used a cross‐sectional design (Hiramatsu 2021‐JPN; Munro 2017‐GBR; Tozawa‐Ono 2021‐JPN), one of which reported no cases of CIN3 in the HPV vaccine‐exposed group (Hiramatsu 2021‐JPN). The other two studies reported a reduced risk of CIN3 following HPV vaccination but with confidence intervals that included no difference (Table 21).
Five studies were pre‐post vaccine introduction studies (Baldur‐Felskov 2015‐DNK; Benard 2017‐USA; Cuschieri 2023‐GBR; Donken 2021‐CAN; Goodman 2024‐DEU). One study reported an increased incidence of CIN3 between 1999 and 2009 (Baldur‐Felskov 2015‐DNK), while another reported a decrease for the youngest female age group (15 to 19 years) and an increase for the oldest group (25 to 29 years) (Benard 2017‐USA). Three other studies reported a decrease in CIN3 incidence comparing time periods before and after HPV vaccine introduction (Cuschieri 2023‐GBR; Donken 2021‐CAN; Goodman 2024‐DEU) (Table 21).
Cervical intraepithelial neoplasia grade 2 and above (CIN2+)
See Table 23 for effect estimates and Table 24 for the risk of bias summary of included studies on CIN2+. HPV vaccination probably reduces the incidence of CIN2+ (moderate‐certainty evidence; Table 1).
21. Primary clinical outcomes effect estimates: CIN2+.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Brotherton 2019‐AUS | Gardasil (Merck quadrivalent) | Female, 12 to 15 years |
Vaccinated: 174,995 Unvaccinated: 48,845 |
Hazard ratio (3 doses, medium‐term) | 0.59 (0.54 to 0.65) | Age, area of residence and socioeconomic status | Cohort |
| Brotherton 2019‐AUS | Gardasil (Merck quadrivalent) | Female, 12 to 15 years |
Vaccinated: 18,190 Unvaccinated: 48,845 |
Hazard ratio (2 doses, medium‐term) | 0.61 (0.52 to 0.72) | Age, area of residence and socioeconomic status | Cohort |
| Brotherton 2019‐AUS | Gardasil (Merck quadrivalent) | Female, 12 to 15 years |
Vaccinated: 8618 Unvaccinated: 48,845 |
Hazard ratio (1 dose, medium‐term) | 0.65 (0.52 to 0.81) | Age, area of residence and socioeconomic status | Cohort |
| Castle 2019‐USA | Gardasil (Merck quadrivalent) | Female, < 18 years | Vaccinated: 3911 Unvaccinated: 59,860 |
Risk ratio (medium‐term) | 0.46 (0.29 to 0.75) | Unadjusted | Cohort |
| Castle 2019‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 20 years | Vaccinated: 5999 Unvaccinated: 59,860 |
Risk ratio (medium‐term) | 0.86 (0.65 to 1.15) | Unadjusted | Cohort |
| Castle 2019‐USA | Gardasil (Merck quadrivalent) | Female, 21 to 24 years | Vaccinated: 5238 Unvaccinated: 59,860 |
Risk ratio (medium‐term) | 1.86 (1.50 to 2.31) | Unadjusted | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, < 16 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (long‐term) | 0.23 (0.11 to 0.49) | Attained age, mother’s education, country | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 17 to 19 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (long‐term) | 0.65 (0.41 to 1.03) | Attained age, mother’s education, country | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 20 to 29 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (long‐term) | 1.31 (0.97 to 1.76) | Attained age, mother’s education, country | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, < 16 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (2 doses, long‐term) | 0.44 (0.10 to 2.03) | Attained age, mother’s education, country | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 17 to 19 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (2 doses, long‐term) | 0.65 (0.25 to 1.74) | Attained age, mother’s education, country | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 20 to 29 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (2 doses, long‐term) | 1.56 (1.15 to 2.11) | Attained age, mother’s education, country | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, < 16 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (1 dose, long‐term) | 0.23 (0.01 to 5.24) | Attained age, mother’s education, country | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 17 to 19 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (1 dose, long‐term) | 0.58 (0.15 to 2.19) | Attained age, mother’s education, country | Cohort |
| Dehlendorff 2018‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 20 to 29 years | Vaccinated: 2,253,561 Unvaccinated: 2,091,579 |
Incidence rate ratio (1 dose, long‐term) | 1.56 (1.13 to 2.15) | Attained age, mother’s education, country | Cohort |
| Del Mistro 2021‐ITA | Gardasil (Merck quadrivalent) | Female, 15 to 25 years | Vaccinated: 4718 Unvaccinated: 91,512 |
Risk ratio (long‐term) | 0.66 (0.41 to 1.06) | Unadjusted | Cohort |
| Donken 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 9 to 14 years | Vaccinated: 18,975 Unvaccinated: 14,130 |
Incidence rate ratio (long‐term) | 0.42 (0.31 to 0.57) | Birth year, age at first screening | Cohort |
| Herweijer 2016‐SWE | Gardasil (Merck quadrivalent) | Female, 11 to 16 years | Vaccinated: 236,372 Unvaccinated: 1,097,319 |
Incidence rate ratio (long‐term) | 0.25 (0.18 to 0.35) | Age, parental highest education | Cohort |
| Herweijer 2016‐SWE | Gardasil (Merck quadrivalent) | Female, 17 to 19 years | Vaccinated: 236,372 Unvaccinated: 1,097,319 |
Incidence rate ratio (long‐term) | 0.54 (0.46 to 0.64) | Age, parental highest education | Cohort |
| Herweijer 2016‐SWE | Gardasil (Merck quadrivalent) | Female, 20 to 29 years | Vaccinated: 236,372 Unvaccinated: 1,097,319 |
Incidence rate ratio (long‐term) | 0.78 (0.65 to 0.93) | Age, parental highest education | Cohort |
| Innes 2020‐NZL | Gardasil (Merck quadrivalent) | Female, 14 to 20 years | Vaccinated: 134,563 Unvaccinated: 175,748 |
Incidence rate ratio (long‐term) | 0.69 (0.64 to 0.75) | Unadjusted | Cohort |
| Kjaer 2020‐EU | Gardasil (Merck quadrivalent) | Female, 16 to 23 years | Vaccinated: 2121 Unvaccinated: NR |
Vaccine effectiveness (3 doses; long‐term) | 100 (94.7 to 100) | Unadjusted | Cohort |
| Kjaer 2021‐EU | Gardasil9 (Merck quadrivalent) | Female, 16 to 26 years | Vaccinated: 1783 Unvaccinated: NR |
Incidence rate ratio (long‐term) | 0.12 (0.00 to 0.72) | Unadjusted | Cohort; no events in exposed group |
| Lei 2020a‐SWE | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 10 to 16 years | Vaccinated: 25,865 Unvaccinated: 100,400 | Risk ratio (long‐term) | 0.42 (0.37 to 0.46) | Birth cohort | Cohort |
| Lei 2020a‐SWE | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 17 to 22 years | Vaccinated: 26,892 Unvaccinated: 100,400 | Risk ratio (long‐term) | 0.61 (0.56 to 0.67) | Birth cohort | Cohort |
| Martellucci 2022‐ITA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 25 to 30 years | Vaccinated: 1118 Unvaccinated: 3547 |
Odds ratio (3 doses; long‐term) | 0.33 (0.11 to 0.96) | Age at screening test, country of birth, residential area, number of screening tests, and municipality average income | Cohort |
| Martellucci 2022‐ITA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 25 to 30 years | Vaccinated: 1118 Unvaccinated: 3547 |
Odds ratio (at least 1 dose; long‐term) | 0.31 (0.11 to 0.91) | Age at screening test, country of birth, residential area, number of screening tests, and municipality average income | Cohort |
| Orumaa 2024‐NOR | Gardasil (Merck quadrivalent) | Female, 16 to 30 years | Vaccinated: 626 Unvaccinated: 18,098 |
Incidence rate ratio (medium‐term) | 0.39 (0.36 to 0.43) | Age, calendar year | Cohort |
| Orumaa 2024‐NOR | Gardasil (Merck quadrivalent) | Female, < 17 years at vaccination | Vaccinated: 225 Unvaccinated: 18,098 |
Incidence rate ratio (medium‐term) | 0.18 (0.16 to 0.21) | Age, calendar year | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 14 years | Vaccinated: 3784 Unvaccinated: 5844 |
Hazard ratio (3 doses; medium‐term) | 0.71 (0.37 to 1.38) | Age, census region, STD history, pregnancy history | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 19 years | Vaccinated: 24,018 Unvaccinated: 39,264 |
Hazard ratio (3 doses; medium‐term) | 0.66 (0.55 to 0.80) | Age, census region, STD history, pregnancy history | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, > 20 years | Vaccinated: 11,021 Unvaccinated: 21,433 |
Hazard ratio (3 doses; medium‐term) | 0.96 (0.77 to 1.20) | Age, census region, STD history, pregnancy history | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 14 years | Vaccinated: 1230 Unvaccinated: 5844 |
Hazard ratio (2 doses; medium‐term) | 0.46 (0.13 to 1.62) | Age, census region, STD history, pregnancy history | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 19 years | Vaccinated: 8147 Unvaccinated: 39,264 |
Hazard ratio (2 doses; medium‐term) | 0.72 (0.54 to 0.95) | Age, census region, STD history, pregnancy history | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, > 20 years | Vaccinated: 4711 Unvaccinated: 21,433 |
Hazard ratio (2 doses; medium‐term) | 1.02 (0.75 to 1.38) | Age, census region, STD history, pregnancy history | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 14 years | Vaccinated: 830 Unvaccinated: 5844 |
Hazard ratio (1 dose; medium‐term) | 0.87 (0.28 to 2.68) | Age, census region, STD history, pregnancy history | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 19 years | Vaccinated: 7099 Unvaccinated: 39,264 |
Hazard ratio (1 dose; medium‐term) | 0.64 (0.47 to 0.88) | Age, census region, STD history, pregnancy history | Cohort |
| Rodriguez 2020‐USA | Gardasil (Merck quadrivalent) | Female, > 20 years | Vaccinated: 5701 Unvaccinated: 21,433 |
Hazard ratio (1 dose; medium‐term) | 1.16 (0.89 to 1.52) | Age, census region, STD history, pregnancy history | Cohort |
| Verdoodt 2020‐DNK | Gardasil (Merck quadrivalent) | Female, < 16 years | Vaccinated: 215,309 Unvaccinated: 374,774 |
Incidence rate ratio (long‐term) | 0.43 (0.36 to 0.51) | Attained age, socioeconomic position | Cohort |
| Yagi 2019‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 7389 Unvaccinated: 7872 |
Risk ratio (long‐term) | 0.18 (0.04 to 0.79) | Unadjusted | Cohort |
| Crowe 2014‐AUS | Gardasil (Merck quadrivalent) | Female, NR | Cases: 1062 Controls: 96,404 |
Odds ratio (3 doses, medium‐term) | 0.54 (0.43 to 0.67) | Socioeconomic status, remoteness, year of birth, follow‐up times | Case‐control |
| Crowe 2014‐AUS | Gardasil (Merck quadrivalent) | Female, NR | Cases: 1062 Controls: 96,404 |
Odds ratio (2 doses, medium‐term) | 0.79 (0.64 to 0.98) | Socioeconomic status, remoteness, year of birth, follow‐up times | Case‐control |
| Crowe 2014‐AUS | Gardasil (Merck quadrivalent) | Female, NR | Cases: 1062 Controls: 96,404 |
Odds ratio (1 dose, medium‐term) | 0.95 (0.77 to 1.16) | Socioeconomic status, remoteness, year of birth, follow‐up times | Case‐control |
| Ikeda 2021‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Cases: 217 Controls: 12,296 |
Odds ratio (medium‐term) | 0.25 (0.12 to 0.54) | Unadjusted | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 17 years | Cases: 4005 Controls: 19,881 |
Incidence rate ratio (long‐term) | 0.62 (0.46 to 0.83) | Matched by age, time since first cytology, years of health plan membership | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 20 years | Cases: 4041 Controls: 20,051 |
Incidence rate ratio (long‐term) | 0.76 (0.61 to 0.94) | Matched by age, time since first cytology, years of health plan membership | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, ≥ 21 years | Cases: 4167 Controls: 20,571 |
Incidence rate ratio (long‐term) | 0.98 (0.84 to 1.13) | Matched by age, time since first cytology, years of health plan membership | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 21 years | Cases: 4025 Controls: 19,882 |
Incidence rate ratio (2 doses; long‐term) | 1.02 (0.82 to 1.28) | Matched by age, time since first cytology, years of health plan membership | Case‐control |
| Silverberg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 21 years | Cases: 4046 Controls: 20,003 |
Incidence rate ratio (1 dose; long‐term) | 0.89 (0.73 to 1.09) | Matched by age, time since first cytology, years of health plan membership | Case‐control |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2019 Unvaccinated: 1484 |
Risk ratio (3 doses; long‐term) | 0.06 (0.00 to 1.01) | Unadjusted | RCT extension; no events in exposed group |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2166 Unvaccinated: 1484 |
Risk ratio (2 doses; long‐term) | 0.05 (0.00 to 0.94) | Unadjusted | RCT extension; no events in exposed group |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2858 Unvaccinated: 1484 |
Risk ratio (1 dose; long‐term) | 0.08 (0.01 to 0.72) | Unadjusted | RCT extension |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 1365 Unvaccinated: 1783 | Incidence rate ratio (long‐term) | 0.026 (0.004 to 0.12) | Age‐ and location‐matched | RCT extension |
| Dorton 2015‐USA | Gardasil (Merck quadrivalent) | Female, ≤ 26 years* |
Vaccinated: 481 Unvaccinated: 911 | Risk ratio (long‐term) | 0.71 (0.58 to 0.89) | Unadjusted | Cross‐sectional; *age at outcome |
| Hikari 2022‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 20 to 24 years | Vaccinated: 2467 Unvaccinated: 4786 | Odds ratio (long‐term) | 0.46 (0.21 to 1.00) | Smoking | Cross‐sectional |
| Hiramatsu 2021‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female 12 to 18 years | Vaccinated: 170 Unvaccinated: 877 |
Risk ratio (medium‐term) | 0.57 (0.03 to 10.60) | Unadjusted | Cross‐sectional; no events in exposed or unexposed groups |
| Munro 2017‐GBR | Cervarix (GSK bivalent; Gardasil (Merck quadrivalent) | Female 20 to 25 years* | Vaccinated: 69 Unvaccinated: 286 |
Risk ratio (long‐term) | 0.60 (0.35 to 1.01) | Unadjusted | Cross‐sectional; *age at outcome |
| Muresu 2022‐ITA | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 24 to 64 years | Vaccinated: 311 Unvaccinated: 875 |
Odds ratio (medium‐term) | 1.13 (0.42 to 3.04) | Age, age at first vaccine dose, education, civil status | Cross‐sectional |
| Ozawa 2017‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 1002 Unvaccinated: 4922 | Risk ratio (long‐term) | 0.25 (0.02 to 4.44) | Unadjusted | Cross‐sectional; no events in exposed group |
| Shiko 2020‐JPN | Cervarix (GSK bivalent) | Female, 12 to 16 years | Vaccinated: 3770 Unvaccinated: 30,511 | Risk ratio (medium‐term) | 0.24 (0.10 to 0.60) | Age, place of screening | Cross‐sectional |
| Tanaka 2017‐JPN | Cervarix (GSK bivalent) | Female, 12 to 16 years | Vaccinated: 413 Unvaccinated: 2012 | Risk ratio (long‐term) | 0.26 (0.02 to 4.41) | Unadjusted | Cross‐sectional; no cases in exposed group |
| Tozawa‐Ono 2021‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 3102 Unvaccinated: 8611 | Risk ratio (medium‐term) | 0.86 (0.46 to 1.60) | Unadjusted | Cross‐sectional |
| Wright 2019‐USA | Gardasil (Merck quadrivalent) | Female, 11 to 26 years | Vaccinated: 2977 Unvaccinated: 11,176 | Odds ratio (medium‐term) | 0.80 (0.60 to 1.10) | Age | Cross‐sectional |
| Baldur‐Felskov 2014‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 26 years | Pre‐vaccine: 2,302,441 Post‐vaccine: 2,431,726 |
Risk ratio (long‐term; 2000 vs 2012) | 1.58 (1.52 to 1.64) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Cruickshank 2017‐GBR | Cervarix (GSK bivalent; Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Pre‐vaccine: 1344 Post‐vaccine: 5669 |
Risk ratio (long‐term; 2008‐9 vs 2009‐2014) | 0.88 (0.81 to 0.95) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Cuschieri 2023‐GBR | Cervarix (GSK bivalent) | Female, 20 to 25 years | Pre‐vaccine: 397 Post‐vaccine: 1309 |
Odds ratio (long‐term; 2011 vs 2017) | 0.3 (0.2 to 0.4) | Diagnosis year, year of birth, deprivation quintile | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years | 4191 cases | Average annual percent change (2008 to 2016) | ‐8.4% (‐12.1 to ‐4.7) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years | 6585 cases | Average annual percent change (2008 to 2016) | 2.6% (0.4 to 4.8) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 34 years | 4805 cases | Average annual percent change (2008 to 2016) | 6.4% (1.1 to 11.9) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 35 to 39 years | 2753 cases | Average annual percent change (2008 to 2016) | 8.9% (4.1 to 13.9) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years | 4191 cases | Incidence rate ratio (2008‐2009 vs 2015‐2016) | 0.49 (0.42 to 0.56) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years | 6585 cases | Incidence rate ratio (2008‐2009 vs 2015‐2016) | 1.20 (1.09 to 1.31) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 34 years | 4805 cases | Incidence rate ratio (2008‐2009 vs 2015‐2016) | 1.60 (1.43 to 1.79) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Gargano 2023‐USA | Gardasil (Merck quadrivalent) | Female, 35 to 39 years | 2753 cases | Incidence rate ratio (2008‐2009 vs 2015‐2016) | 1.97 (1.70 to 2.29) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Goodman 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 28 to 33 years | Pre‐vaccine: 22,533 Post‐vaccine: 38,987 |
Relative risk (long‐term) | 0.49 (0.39 to 0.62) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Rebolj 2022‐GBR | Cervarix (GSK bivalent); | Female, 24 to 25 years | N = 64,274 | Vaccine effectiveness (long‐term) | 72% (66 to 77) | Deprivation and laboratory | Pre‐ vs post‐vaccine introduction |
| Thamsborg 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 15 years | Pre‐vaccine: 19,629 Post‐vaccine: 26,215 |
Incidence rate ratio (long‐term; 1999‐2008 vs 2009‐2018) | 0.74 (0.66 to 0.82) | Unadjusted | Pre‐ vs post‐vaccine introduction |
CIN2+: cervical intraepithelial neoplasia grade 2 or higher; NR: not reported; RCT: randomised controlled trial; STD: sexually transmitted disease
22. Risk of bias summary: CIN2+.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Brotherton 2019‐AUS | Serious | Serious | Low | Low | Moderate | Low | Moderate | Serious |
| Castle 2019‐USA | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Dehlendorff 2018‐DNK/SWE | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Del Mistro 2021‐ITA | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Donken 2021‐CAN | Serious | Low | Serious | Low | Moderate | Low | Low | Serious |
| Herweijer 2016‐SWE | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Innes 2020‐NZL | Critical | Serious | Low | Low | Moderate | Low | Moderate | Critical |
| Kjaer 2020‐EU | Critical | Serious | Low | Low | Moderate | Low | Low | Critical |
| Kjaer 2021‐EU | Critical | Serious | Low | Low | Moderate | Low | Low | Critical |
| Martellucci 2022‐ITA | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Orumaa 2024‐NOR | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Rodriguez 2020‐USA | Moderate | Low | Low | Low | Low | Low | Low | Moderate |
| Verdoodt 2020‐DNK | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Yagi 2019‐JPN | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Crowe 2014‐AUS | Serious | Serious | Low | Low | Low | Low | Low | Serious |
| Ikeda 2021‐JPN | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Silverberg 2018‐USA | Serious | Serious | Low | Low | Low | Low | Low | Serious |
| Sankaranarayanan 2018‐IND | Moderate | Low | Low | Low | Moderate | Low | Low | Moderate |
| Kreimer 2011‐CRI | Moderate | Moderate | Low | Low | Moderate | Low | Low | Moderate |
| Dorton 2015‐USA | Critical | Serious | Moderate | Low | Moderate | Low | Moderate | Critical |
| Hikari 2022‐JPN | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Hiramatsu 2021‐JPN | Critical | Serious | Low | Low | Moderate | Low | Low | Critical |
| Lei 2020a‐SWE | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Munro 2017‐GBR | Critical | Low | Low | Low | Serious | Low | Low | Critical |
| Muresu 2022‐ITA | Serious | Low | Serious | No information | Moderate | Low | Low | Serious |
| Ozawa 2017‐JPN | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Shiko 2020‐JPN | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Tanaka 2017‐JPN | Critical | Moderate | Moderate | Low | Serious | Low | Low | Critical |
| Tozawa‐Ono 2021‐JPN | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Wright 2019‐USA | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Baldur‐Felskov 2014‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Cruickshank 2017‐GBR | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Cuschieri 2023‐GBR | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Gargano 2023‐USA | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Goodman 2024‐DEU | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Rebolj 2022‐GBR | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Thamsborg 2020‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
CIN2+: cervical intraepithelial neoplasia grade 2 or higher
Thirty‐seven studies were identified that reported on CIN2+ following HPV vaccination (Baldur‐Felskov 2014‐DNK; Brotherton 2019‐AUS; Castle 2019‐USA; Crowe 2014‐AUS; Cruickshank 2017‐GBR; Cuschieri 2023‐GBR; Dehlendorff 2018‐DNK/SWE; Del Mistro 2021‐ITA; Donken 2021‐CAN; Dorton 2015‐USA; Gargano 2023‐USA; Goodman 2024‐DEU; Herweijer 2016‐SWE; Hikari 2022‐JPN; Hiramatsu 2021‐JPN; Ikeda 2021‐JPN; Innes 2020‐NZL; Kjaer 2020‐EU; Kjaer 2021‐EU; Kreimer 2011‐CRI; Lei 2020a‐SWE; Martellucci 2022‐ITA; Munro 2017‐GBR; Muresu 2022‐ITA; Orumaa 2024‐NOR; Ozawa 2017‐JPN; Rebolj 2022‐GBR; Rodriguez 2020‐USA; Sankaranarayanan 2018‐IND; Shiko 2020‐JPN; Silverberg 2018‐USA; Tanaka 2017‐JPN; Thamsborg 2020‐DNK; Tozawa‐Ono 2021‐JPN; Verdoodt 2020‐DNK; Wright 2019‐USA; Yagi 2019‐JPN).
Fifteen were cohort studies (Brotherton 2019‐AUS; Castle 2019‐USA; Dehlendorff 2018‐DNK/SWE; Del Mistro 2021‐ITA; Donken 2021‐CAN; Herweijer 2016‐SWE; Innes 2020‐NZL; Kjaer 2020‐EU; Kjaer 2021‐EU; Lei 2020a‐SWE; Martellucci 2022‐ITA; Orumaa 2024‐NOR; Rodriguez 2020‐USA; Verdoodt 2020‐DNK; Yagi 2019‐JPN), three were case‐control studies (Crowe 2014‐AUS; Ikeda 2021‐JPN; Silverberg 2018‐USA), two were RCT extensions (Kreimer 2011‐CRI; Sankaranarayanan 2018‐IND), 10 were cross‐sectional studies (Dorton 2015‐USA; Hikari 2022‐JPN; Hiramatsu 2021‐JPN; Munro 2017‐GBR; Muresu 2022‐ITA; Ozawa 2017‐JPN; Shiko 2020‐JPN; Tanaka 2017‐JPN; Tozawa‐Ono 2021‐JPN; Wright 2019‐USA), and seven were pre‐post vaccine introduction studies (Baldur‐Felskov 2014‐DNK; Cruickshank 2017‐GBR; Cuschieri 2023‐GBR; Gargano 2023‐USA; Goodman 2024‐DEU; Rebolj 2022‐GBR; Thamsborg 2020‐DNK).
One of the cohort studies did not report any cases of CIN2+ in the HPV vaccine‐exposed group (Kjaer 2021‐EU). When pooled, the cohort studies indicated a reduction of CIN2+ incidence following HPV vaccination of 38% in the medium term (RR 0.62, 95% CI 0.45 to 0.85; 3 cohort studies, 347,928 females; I2 = 95%) and 49% in the long term (RR 0.51, 95% CI 0.41 to 0.64; 6 cohort studies, 6,464,506 females; I2 = 91%) (Analysis 1.8). This decrease was 62% in the long term when limited to those receiving the HPV vaccine before age 16 years (RR 0.38, 95% CI 0.31 to 0.45; 5 cohort studies, 6,455,176 females; I2 = 64%) (Analysis 1.9).
1.8. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 8: CIN2+ (cohort studies; medium/long‐term)
1.9. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 9: CIN2+ (cohort studies; medium/long‐term; ≤ 16 years at vaccination)
The case‐control studies all reported decreased odds of CIN2+ following HPV vaccination (Crowe 2014‐AUS; Ikeda 2021‐JPN; Silverberg 2018‐USA) (Table 23).
Of the two RCT extension studies, one did not identify any cases of CIN2+ in the HPV vaccine‐exposed group (Sankaranarayanan 2018‐IND). The other reported a large decrease of CIN2+ incidence (IRR 0.026, 95% CI 0.004 to 0.12) following HPV vaccination (Kreimer 2011‐CRI) (Table 23).
Of the cross‐sectional studies, three did not report any cases of CIN2+ in the HPV vaccine‐exposed group (Hiramatsu 2021‐JPN; Ozawa 2017‐JPN; Tanaka 2017‐JPN). Four studies reported adjusted estimates (Hikari 2022‐JPN; Muresu 2022‐ITA; Shiko 2020‐JPN; Wright 2019‐USA), which, when pooled, showed a decreased risk of CIN2+ following HPV vaccination of 38% in the medium term (RR 0.62, 95% CI 0.28 to 1.34; 3 cross‐sectional studies, 49,620 females; I2 = 72%) and 54% in the long term (RR 0.46, 95% CI 0.21 to 1.00; 1 cross‐sectional study, 7253 females) (Analysis 1.10). Three additional cross‐sectional studies reported only unadjusted estimates (Dorton 2015‐USA; Munro 2017‐GBR; Tozawa‐Ono 2021‐JPN).
1.10. Analysis.
Comparison 1: Primary clinical outcomes, Outcome 10: CIN2+ (cross‐sectional studies; medium/long‐term)
One pre‐post vaccine introduction study reported an increase in CIN2+ incidence between 2000 and 2012 (Baldur‐Felskov 2014‐DNK), while the other six reported a reduced incidence (Cruickshank 2017‐GBR; Cuschieri 2023‐GBR; Gargano 2023‐USA; Goodman 2024‐DEU; Rebolj 2022‐GBR; Thamsborg 2020‐DNK) (Table 23).
Six studies were identified that reported on the effectiveness of two doses or one dose of HPV vaccine against CIN2+ (Brotherton 2019‐AUS; Crowe 2014‐AUS; Dehlendorff 2018‐DNK/SWE; Rodriguez 2020‐USA; Sankaranarayanan 2018‐IND; Silverberg 2018‐USA). Effectiveness was inconsistent across studies, with four studies indicating a reduction of CIN2+ following two doses in some age groups (Brotherton 2019‐AUS; Crowe 2014‐AUS; Rodriguez 2020‐USA; Sankaranarayanan 2018‐IND), while two did not. Three studies indicated a reduction of CIN2+ following one dose of HPV vaccine (Brotherton 2019‐AUS; Rodriguez 2020‐USA; Sankaranarayanan 2018‐IND).
Cervical intraepithelial neoplasia grade 2 (CIN2)
See Table 25 for effect estimates and Table 26 for the risk of bias summary of included studies on CIN2. HPV vaccination probably reduces the incidence of CIN2 (moderate‐certainty evidence; Table 12).
23. Primary clinical outcomes effect estimates: CIN2.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Donken 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 9 to 14 years | Vaccinated: 18,975 Unvaccinated: 14,130 |
Incidence rate ratio (long‐term) | 0.59 (0.40 to 0.88) | Birth year, age at first screening | Cohort |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 12 to 13 years | NR | Odds ratio (3 doses; long‐term) | 0.11 (0.06 to 0.19) | Deprivation, rurality | Cohort |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 12 to 18+ years | NR | Odds ratio (2 doses; long‐term) | 0.70 (0.45 to 1.07) | Deprivation, rurality | Cohort |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 12 to 18+ years | NR | Odds ratio (1 dose; long‐term) | 0.95 (0.56 to 1.59) | Deprivation, rurality | Cohort |
| Paraskevaidis 2020‐GRC | NR | Female, NR | Vaccinated: 849 Unvaccinated: 849 |
Risk ratio (long‐term) | 0.04 (0.01 to 0.30) | Unadjusted | Cohort |
| Yagi 2019‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 7389 Unvaccinated: 7872 |
Risk ratio (long‐term) | 0.43 (0.08 to 2.20) | Unadjusted | Cohort |
| Ikeda 2021‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Cases: 165 Controls: 12,296 |
Odds ratio (medium‐term) | 0.57 (0.36 to 0.90) | Unadjusted | Case‐control |
| Munro 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female 20 to 25 years* | Vaccinated: 67 Unvaccinated: 294 |
Risk ratio (long‐term) | 0.72 (0.37 to 1.39) | Unadjusted | Cross‐sectional; *age at outcome |
| Tozawa‐Ono 2021‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 3102 Unvaccinated: 8611 |
Risk ratio (medium‐term) | 0.99 (0.48 to 2.04) | Unadjusted | Cross‐sectional |
| Benard 2017‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 19 years* | 421 cases | Annual percent change (long‐term; 2007 vs 2014) | ‐10.5% (‐18.8% to ‐1.2%) | Changes in cervical screening | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Benard 2017‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | 2028 cases | Annual percent change (long‐term; 2007 vs 2014) | ‐6.3% (‐10.9% to ‐1.4%) | Changes in cervical screening | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Benard 2017‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years* | 1847 cases | Annual percent change (long‐term; 2007 vs 2014) | 1.9% (‐1.6% to 5.5%) | Changes in cervical screening | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Cuschieri 2023‐GBR | Cervarix (GSK bivalent) | Female, 20 to 25 years* | Pre‐vaccine: 397 Post‐vaccine: 1309 |
Odds ratio (long‐term; 2011 vs 2017) | 0.32 (0.21 to 0.48) | Diagnosis year, year of birth, deprivation quintile | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Goodman 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female 28 to 33 years | Pre‐vaccine: 22,533 Post‐vaccine: 38,987 |
Relative risk (long‐term) | 0.85 (0.53 to 1.39) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Thamsborg 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 15 years | Pre‐vaccine: 19,629 Post‐vaccine: 26,215 |
Incidence rate ratio (long‐term; 1999‐2008 vs 2009‐2018) | 0.82 (0.68 to 0.96) | Unadjusted | Pre‐ vs post‐vaccine introduction |
CIN2: cervical intraepithelial neoplasia grade 2; NR: not reported
24. Risk of bias summary: CIN2.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Donken 2021‐CAN | Serious | Low | Serious | Low | Moderate | Low | Low | Serious |
| Palmer 2019‐GBR | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Paraskevaidis 2020‐GRC | Critical | Serious | Serious | Low | Serious | Low | Moderate | Critical |
| Yagi 2019‐JPN | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Ikeda 2021‐JPN | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Munro 2017‐GBR | Critical | Low | Low | Low | Serious | Low | Low | Critical |
| Tozawa‐Ono 2021‐JPN | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Benard 2017‐USA | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Cuschieri 2023‐GBR | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Goodman 2024‐DEU | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Thamsborg 2020‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
CIN2: cervical intraepithelial neoplasia grade 2
Eleven studies were identified that reported on CIN2 following HPV vaccination (Benard 2017‐USA; Cuschieri 2023‐GBR; Donken 2021‐CAN; Goodman 2024‐DEU; Ikeda 2021‐JPN; Munro 2017‐GBR; Palmer 2019‐GBR; Paraskevaidis 2020‐GRC; Thamsborg 2020‐DNK; Tozawa‐Ono 2021‐JPN; Yagi 2019‐JPN).
Four were cohort studies (Donken 2021‐CAN; Palmer 2019‐GBR; Paraskevaidis 2020‐GRC; Yagi 2019‐JPN), one was a case‐control study (Ikeda 2021‐JPN), two were cross‐sectional (Munro 2017‐GBR; Tozawa‐Ono 2021‐JPN), and four were pre‐post vaccine introduction studies (Benard 2017‐USA; Cuschieri 2023‐GBR; Goodman 2024‐DEU; Thamsborg 2020‐DNK).
Of the cohort studies, one reported a decreased incidence of CIN2 following HPV vaccination (IRR 0.59, 95% CI 0.40 to 0.88; 33,105 females) (Donken 2021‐CAN), while another reported a reduced odds of CIN2 (OR 0.11, 95% CI 0.06 to 0.19) (Palmer 2019‐GBR). The other two cohort studies also reported a decreased risk of CIN2, but the effects were not adjusted for confounding (Paraskevaidis 2020‐GRC; Yagi 2019‐JPN) (Table 25).
The case‐control study reported a reduced odds of CIN2 following HPV vaccination (Ikeda 2021‐JPN).
Both cross‐sectional studies reported a reduced risk of CIN2 following HPV vaccination, but with confidence intervals that included no difference (Munro 2017‐GBR; Tozawa‐Ono 2021‐JPN).
All four pre‐post vaccine introduction studies reported a reduced risk of CIN2 comparing time periods before and after HPV vaccine introduction (Benard 2017‐USA; Cuschieri 2023‐GBR; Goodman 2024‐DEU; Thamsborg 2020‐DNK) (Table 25).
One study reported on the effectiveness of two doses or one dose of HPV vaccine on CIN2 (Palmer 2019‐GBR). While the estimates indicated a reduced odds of CIN2, the confidence intervals included no difference.
Vaginal intraepithelial neoplasia (VaIN)
See Table 27 for effect estimates and Table 28 for the risk of bias summary of included studies on VaIN. HPV vaccination may reduce VaIN incidence (low‐certainty evidence; Table 12).
25. Primary clinical outcomes effect estimates: VaIN.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Mix 2022‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 29 years* | 945 cases of VaIN | Annual percent change (medium‐term; 2000 vs 2017) | ‐9.3% (‐11.5% to ‐7.0%) | Weighted to national population | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Mix 2022‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 39 years * | 945 cases of VaIN | Annual percent change (long‐term; 2000 vs 2017) | ‐0.6% (‐4.2% to 3.2%) | Weighted to national population | Pre‐ vs post‐vaccine introduction; *age at outcome |
VaIN: vaginal intraepithelial neoplasia
26. Risk of bias summary: VaIN.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Mix 2022‐USA | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
VaIN: vaginal intraepithelial neoplasia
One study was included that reported on VaIN following HPV vaccination (Mix 2022‐USA). This study had a pre‐post vaccine introduction design and reported a decrease in VaIN in 15‐ to 29‐year‐olds between 2000 and 2017. A smaller decrease was also seen in 30‐ to 39‐year‐olds, but confidence intervals included no difference (Table 27).
Vulval intraepithelial neoplasia (VIN)
See Table 29 for effect estimates and Table 30 for the risk of bias summary of included studies on VIN. We do not know about the effect of HPV vaccine on VIN incidence because the certainty of the evidence is very low (very low‐certainty evidence; Table 12).
27. Primary clinical outcomes effect estimates: VIN.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Mix 2022‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 29 years* | 6128 cases of VIN | Annual percent change (medium‐term; 2000 vs 2017) | ‐11.7% (‐13.4% to ‐10.0%) | Weighted to national population | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Mix 2022‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 34 years* | 6128 cases of VIN | Annual percent change (long‐term; 2000 vs 2017) | ‐0.5% (‐1.3% to 0.4%) | Weighted to national population | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Rasmussen 2020‐DNK | NR | Female, 12 to 26 years | NR | Annual percentage increase (long‐term; 1997‐1998 vs 2017‐2018) | 2.4% (1.8% to 3.0%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
NR: not reported; VIN: vulval intraepithelial neoplasia
28. Risk of bias summary: VIN.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Mix 2022‐USA | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
| Rasmussen 2020‐DNK | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
VIN: vulval intraepithelial neoplasia
Two studies were included that reported on VIN following HPV vaccination (Mix 2022‐USA; Rasmussen 2020‐DNK).
Both studies had a pre‐post vaccine introduction design. One reported a decrease in VIN in 15‐ to 29‐year‐olds between 2000 and 2017 (Mix 2022‐USA). A smaller decrease was also seen in 30‐ to 34‐year‐olds, but confidence intervals included no difference. The other study reported an increase in VIN incidence between 1997‐1998 and 2017‐2018 (Rasmussen 2020‐DNK) (Table 29).
Anal intraepithelial neoplasia (AIN)
See Table 31 for effect estimates and Table 32 for the risk of bias summary of included studies on AIN. HPV vaccination may reduce the incidence of AIN (low‐certainty evidence; Table 12).
29. Primary clinical outcomes effect estimates: AIN.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Baandrup 2024‐DNK | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 17 to 32 years | 30 cases of AIN | Hazard ratio (long‐term) | 0.59 (0.35 to 0.99) | Maximum level of own, mother’s and father’s education | Cohort |
| Baandrup 2024‐DNK | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, < 17 years at vaccination | < 5 cases of AIN | Hazard ratio (long‐term) | 0.30 (0.1 to 0.87) | Maximum level of own, mother’s and father’s education | Cohort |
| Baandrup 2024‐DNK | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 17 to 32 years at vaccination | 26 cases of AIN | Hazard ratio (long‐term) | 1.21 (0.73 to 2.03) | Maximum level of own, mother’s and father’s education | Cohort |
| Mix 2022‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 29 years* | 462 cases of AIN | Annual percent change (medium‐term; 2000 vs 2017) | 7.4% (2.9% to 12.1%) | Weighted to national population | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Mix 2022‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 39 years* | 462 cases of AIN | Annual percent change (long‐term; 2000 vs 2017) | 6.3% (4.0% to 8.6%) | Weighted to national population | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Mix 2022‐USA | Gardasil (Merck quadrivalent) | Male, 15 to 29 years* | 2154 cases of AIN | Annual percent change (medium‐term; 2000 vs 2017) | 16.7% (10.1% to 23.8%) | Weighted to national population | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Mix 2022‐USA | Gardasil (Merck quadrivalent) | Male, 30 to 39 years* | 2154 cases of AIN | Annual percent change (long‐term; 2000 vs 2017) | 3.6% (1.7% to 5.6%) | Weighted to national population | Pre‐ vs post‐vaccine introduction; *age at outcome |
AIN: anal intraepithelial neoplasia
30. Risk of bias summary: AIN.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Baandrup 2024‐DNK | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Mix 2022‐USA | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
AIN: anal intraepithelial neoplasia
Two studies were included that reported on AIN following the introduction of HPV vaccination (Baandrup 2024‐DNK; Mix 2022‐USA). One cohort study reported a reduced risk of AIN with HPV vaccination in females, with a more pronounced effect in females vaccinated before 17 years of age (Baandrup 2024‐DNK). The other study had a pre‐post vaccine introduction design and reported an increase in AIN incidence in males and females between 2000 and 2017 (Mix 2022‐USA) (Table 31).
Specific adverse events
Postural orthostatic tachycardia syndrome (POTS)
See Table 33 for effect estimates and Table 34 for the risk of bias summary of included studies on POTS. HPV vaccination likely does not increase the risk of POTS (moderate‐certainty evidence; Table 2).
31. Specific adverse events effect estimates: postural orthostatic tachycardia syndrome (POTS).
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 55,774 person‐years Unvaccinated: 244,171 person‐years |
Hazard ratio (short‐term) | 1.40 (0.50 to 3.87) | Hospital district, country background, number of any hospital visits or admissions | Cohort |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 186,946 person‐years Unvaccinated: 244,171 person‐years |
Hazard ratio (medium‐term) | 0.99 (0.46 to 2.11) | Hospital district, country background, number of any hospital visits or admissions | Cohort |
| Thomsen 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 11 to 17 years | Vaccinated: 313,880 person‐years Unvaccinated: 313,871 person‐years |
Incidence rate ratio (short‐term) | 0.54 (0.19 to 1.53) | Age, calendar year of cohort entry, histories of hospital‐diagnosed asthma, diabetes, infections, and mental disorders, number of general practitioner contacts within the past 5 years, previous psychometric tests or talk therapy with a general practitioner, a previous psychologist or psychiatrist visit in primary care, parental education, parental employment status, parental annual income, parental marital status, and parental ethnicity | Cohort |
| Hviid 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 27 years | Reference period: 179 cases, 1393 person‐years Risk period: 19 cases, 226 person‐years |
Rate ratio (medium‐term) | 0.86 (0.48 to 1.54) | Age, season | Self‐controlled case series |
32. Risk of bias summary: postural orthostatic tachycardia syndrome (POTS).
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Skufca 2018‐FIN | Serious | Low | Low | Low | Moderate | Moderate | Moderate | Serious |
| Thomsen 2020‐DNK | Moderate | Low | Low | Low | Low | Low | Moderate | Moderate |
| Study | Case definition | Case ascertainment independent? | Exposure | Co‐interventions | Observation period defined | Risk period defined | Comparability | Overall |
| Hviid 2020‐DNK | Yes, ICD‐10 codes | Not reported | Yes, Danish vaccination register | Unclear | Yes, before and after risk period | Yes, 365 days post vaccine | Yes, adjusted for age and season | Low |
ICD‐10: International Statistical Classification of Diseases and Related Health Problems (10th Revision)
Three studies were included that reported on postural orthostatic tachycardia syndrome (POTS) following HPV vaccination (Hviid 2020‐DNK; Skufca 2018‐FIN; Thomsen 2020‐DNK). Two were retrospective cohort studies (Skufca 2018‐FIN; Thomsen 2020‐DNK) and one was a self‐controlled case series analysis (Hviid 2020‐DNK).
Two cohort studies reported on short‐term follow‐up from HPV vaccination and there was no association between HPV vaccination and POTS (RR 0.87, 95% CI 0.34 to 2.22; 2 studies, 927,696 person‐years; I2 = 39%) (Skufca 2018‐FIN; Thomsen 2020‐DNK) (Analysis 2.1). One study reported that in a medium‐term follow‐up there was also no association between HPV vaccination and POTS (HR 0.99, 95% CI 0.46 to 2.12; 1 study, 431,117 person‐years) (Skufca 2018‐FIN) (Analysis 2.1). No studies were identified that reported on the association between HPV vaccination and POTS in the long term.
2.1. Analysis.
Comparison 2: Specific adverse events, Outcome 1: Postural orthostatic tachycardia syndrome (cohort studies)
In a self‐controlled case series analysis (Hviid 2020‐DNK), there was no increase in the rate of POTS following HPV vaccination (1 study, 198 cases of POTS; incidence rate ratio (IRR) 0.86, 95% CI 0.48 to 1.54) (Table 33).
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
See Table 35 for effect estimates and Table 36 for the risk of bias summary of included studies on CFS/ME. HPV vaccination likely does not increase the risk of CFS/ME (moderate‐certainty evidence; Table 2).
33. Specific adverse events effect estimates: chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Thomsen 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 11 to 17 years | Vaccinated: 313,879 Unvaccinated: 313,859 |
Incidence rate ratio (short‐term) | 0.12 (0.02 to 0.99) | Age, calendar year of cohort entry, histories of hospital‐diagnosed asthma, diabetes, infections and mental disorders, number of general practitioner contacts within the past 5 years, previous psychometric tests or talk therapy with a general practitioner, a previous psychologist or psychiatrist visit in primary care, parental education, parental employment status, parental annual income, parental marital status and parental ethnicity | Cohort |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 55,834 person‐years Unvaccinated: 244,438 person‐years |
Hazard ratio (short‐term) | 0.61 (0.42 to 0.91) | Hospital district, country background, number of any hospital visits or admissions | Cohort |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 186,946 person‐years Unvaccinated: 244,171 person‐years |
Hazard ratio (medium‐term) | 0.75 (0.59 to 0.95) | Hospital district, country background, number of any hospital visits or admissions | Cohort |
| Feiring 2017‐NOR | Gardasil (Merck quadrivalent) | Female, 11 to 12 years | Vaccinated: 56,334 person‐years Unvaccinated: 74,735 person‐years |
Incidence rate ratio (short‐term) | 0.97 (0.51 to 1.82) | Unadjusted | Cohort |
| Feiring 2017‐NOR | Gardasil (Merck quadrivalent) | Female, 11 to 17 years | Vaccinated: 346,717 person‐years Unvaccinated: 156,475 person‐years |
Hazard ratio (medium‐term) | 0.86 (0.69 to 1.08) | Parental education level, country background, region of residence, and number of previous hospital contacts. | Cohort |
| Tsai 2023‐TWN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 15 years | Vaccinated: 494,296 person‐years Unvaccinated: 2,280,063 person‐years |
Standardised incidence ratio (short‐term) | 0.33 (‐0.5 to 0.61) | Unadjusted | Cohort |
| Tsai 2023‐TWN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 15 years | Vaccinated: 494,296 person‐years Unvaccinated: 2,280,063 person‐years |
Standardised incidence ratio (medium‐term) | 1.37 (0.75 to 2.00) | Unadjusted | Cohort |
| Thomsen 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 11 to 17 years | Reference period: 13 cases Risk period: 11 cases |
Incidence rate ratio (medium‐term) | 0.82 (0.16 to 4.16) | Unadjusted | Self‐controlled case series |
| Hviid 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 27 years | Reference period: 132 cases, 1100 person‐years Risk period: 4 cases, 79 person‐years |
Rate ratio (medium‐term) | 0.38 (0.13 to 1.09) | Age, season | Self‐controlled case series |
| Donegan 2013‐GBR | Cervarix (GSK bivalent) | Female, 12 to 18 years | Reference period: NR Risk period: 161 cases |
Incidence rate ratio (medium‐term) | 1.03 (0.51 to 2.07) | Age, calendar time | Self‐controlled case series |
| Cameron 2016‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Pre‐vaccine: 220,810 Post‐vaccine: 206,323 |
Incidence rate ratio (long‐term; 2004 vs 2012) | 2.68 (0.77 to 11.69) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Cameron 2016‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Male, 12 to 18 years | Pre‐vaccine: 232,479 Post‐vaccine: 216,880 |
Incidence rate ratio (long‐term; 2004 vs 2012) | 2.14 (0.31 to 23.7) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Schurink‐Van't Klooster 2018‐NLD | Cervarix (GSK bivalent) | Female, 12 to 16 years | Pre‐vaccine: 2758 person‐years Post‐vaccine: 57,214 person‐years |
Incidence rate ratio (long‐term; 2007‐8 vs 2009‐13) | 0.24 (0.03 to 2.09) | Age | Pre‐ vs post‐vaccine introduction |
NR: not reported
34. Risk of bias summary: chronic fatigue syndrome/myalgic encephalitis (CFS/ME).
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Thomsen 2020‐DNK | Moderate | Low | Low | Low | Low | Low | Low | Moderate |
| Skufca 2018‐FIN | Serious | Low | Low | Low | Moderate | Moderate | Low | Serious |
| Feiring 2017‐NOR | Moderate | Low | Low | Low | Moderate | Moderate | Low | Moderate |
| Cameron 2016‐GBR | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Schurink‐Van't Klooster 2018‐NLD | Serious | Serious | Serious | Low | Low | Low | Low | Serious |
| Tsai 2023‐TWN | Serious | Serious | Low | Low | Moderate | Low | Low | Serious |
| Study | Case definition | Case ascertainment independent? | Exposure | Co‐interventions | Observation period defined | Risk period defined | Comparability | Overall |
| Thomsen 2020‐DNK | Yes, hospital records | Not reported | Yes, national database | Unclear | Yes, before and after risk period | Yes, 365 days post vaccine | Yes, adjusted for age and calendar time | Low |
| Hviid 2020‐DNK | Yes, ICD‐10 codes | Not reported | Yes, Danish vaccination register | Unclear | Yes, before and after risk period | Yes, 365 days post vaccine | Yes, adjusted for age and season | Low |
| Donegan 2013‐GBR | Yes, with validation | Not reported | Yes, national statistics | Unclear | Yes, before and after risk period | Yes, 365 days post vaccine | Yes, adjusted for age and calendar time | Low |
ICD‐10: International Statistical Classification of Diseases and Related Health Problems (10th Revision)
Eight studies were included that reported on chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) following HPV vaccination (Cameron 2016‐GBR; Donegan 2013‐GBR; Feiring 2017‐NOR; Hviid 2020‐DNK; Schurink‐Van't Klooster 2018‐NLD; Skufca 2018‐FIN; Thomsen 2020‐DNK; Tsai 2023‐TWN). Four studies were retrospective cohort studies (Feiring 2017‐NOR; Skufca 2018‐FIN; Thomsen 2020‐DNK; Tsai 2023‐TWN) and three studies reported self‐controlled case series analyses (Donegan 2013‐GBR; Hviid 2020‐DNK; Thomsen 2020‐DNK). Two studies reported on rates of CFS/ME before and after HPV vaccine introduction (Cameron 2016‐GBR; Schurink‐Van't Klooster 2018‐NLD).
In the short term, three cohort studies reported a reduced risk of CFS/ME following HPV vaccination in the short term (RR 0.40, 95% CI 0.22 to 0.75; 3 studies, 3,702,369 person‐years; I2 = 67%) (Analysis 2.2) (Skufca 2018‐FIN; Thomsen 2020‐DNK; Tsai 2023‐TWN). In the medium term, three cohort studies indicated no difference in risk of CFS/ME following HPV vaccination (RR 0.96, 95% CI 0.67 to 1.39; 3 studies, 3,708,668 person‐years; I2 = 88%) (Analysis 2.2) (Feiring 2017‐NOR; Skufca 2018‐FIN; Tsai 2023‐TWN). No studies were identified that reported on the association between HPV vaccination and CFS/ME in the long term.
2.2. Analysis.
Comparison 2: Specific adverse events, Outcome 2: Chronic fatigue syndrome/myalgic encephalomyelitis (cohort studies; short/medium‐term)
In three self‐controlled case series analyses, each reported no increase in the rate of CFS/ME in the weeks following HPV vaccination (RR 0.74, 95% CI 0.40 to 1.39; 3 studies, 321 cases of CFS/ME; I2 = 15%) (Analysis 2.3) (Donegan 2013‐GBR; Hviid 2020‐DNK; Thomsen 2020‐DNK).
2.3. Analysis.
Comparison 2: Specific adverse events, Outcome 3: Chronic fatigue syndrome/myalgic encephalomyelitis (self‐controlled case series; medium‐term)
Two pre‐ versus post‐vaccine introduction studies reported no association between the introduction of HPV vaccination and the risk of CFS/ME (Cameron 2016‐GBR; Schurink‐Van't Klooster 2018‐NLD).
Paralysis
See Table 37 for effect estimates and Table 38 for the risk of bias summary of included studies on CFS/ME. HPV vaccination likely does not increase the risk of paralysis (moderate‐certainty evidence; Table 2).
35. Specific adverse events effect estimates: paralysis.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Arnheim‐Dahlström 2013‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 12 to 17 years | Vaccinated: 229,574 person‐years Unvaccinated: 2,367,206 person‐years |
Rate ratio (short‐term) | 0.56 (0.35 to 0.90) | Country, age in two‐year intervals, calendar year, and parental country of birth, parental education and paternal socioeconomic status | Cohort |
| Frisch 2018‐DNK | Gardasil (Merck quadrivalent) | Male, 10 to 17 years | Vaccinated: 24,057 person‐years Unvaccinated: 4,315,133 person‐years |
Rate ratio (long‐term) | 0.70 (0.17 to 2.80) | Age and calendar year | Cohort |
| Hviid 2017‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 18 to 44 years | Vaccinated: 319,298 person‐years Unvaccinated: 16,067,162 person‐years |
Rate ratio (short‐term) | 0.52 (0.32 to 0.83) | Age, calendar period and country of residence | Cohort |
| Hviid 2017‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 18 to 44 years | Vaccinated: 319,298 person‐years Unvaccinated: 16,067,162 person‐years |
Rate ratio (medium‐term) | 0.42 (0.20 to 0.89) | Age, calendar period and country of residence | Cohort |
| Hviid 2017‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 18 to 44 years | Vaccinated: 319,298 person‐years Unvaccinated: 16,067,162 person‐years |
Rate ratio (long‐term) | 0.61 (0.34 to 1.10) | Age, calendar period and country of residence | Cohort |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 56,619 person‐years Unvaccinated: 247,695 person‐years |
Hazard ratio (short‐term) | 0.23 (0.03 to 1.81) | Hospital district, country background and number of any hospital visits or admissions two years before the scheduled vaccination | Cohort |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 186,946 person‐years Unvaccinated: 244,171 person‐years |
Hazard ratio (medium‐term) | 0.86 (0.39 to 1.89) | Hospital district, country background and number of any hospital visits or admissions two years before the scheduled vaccination | Cohort |
| Yoon 2021‐KOR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 14 years | Vaccinated: 408,345 person‐years Unvaccinated: 60,626 person‐years |
Rate ratio (short‐term) | 0.68 (0.22 to 2.11) | Age, region of residence, type of health insurance, income level and anaemia | Cohort |
| Yoon 2021‐KOR | Cervarix (GSK bivalent) | Female, 11 to 14 years | Vaccinated: 93,203 person‐years Unvaccinated: 60,626 person‐years |
Risk ratio (short‐term) | 0.45 (0.07 to 2.77) | Age, region of residence, type of health insurance, income level and anaemia | Cohort |
| Yoon 2021‐KOR | Gardasil (Merck quadrivalent) | Female, 11 to 14 years | Vaccinated: 315,079 person‐years Unvaccinated: 60,626 person‐years |
Risk ratio (short‐term) | 0.75 (0.24 to 2.39) | Age, region of residence, type of health insurance, income level and anaemia | Cohort |
| Yoon 2021‐KOR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 14 years | Vaccinated: 790,021 person‐years Unvaccinated: 119,946 person‐years |
Rate ratio (medium‐term) | 0.67 (0.30 to 1.50) | Age, region of residence, type of health insurance, income level and anaemia | Cohort |
| Yoon 2021‐KOR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 14 years | Reference period: 14 cases Risk period: 19 cases |
Risk ratio (medium‐term) | 0.95 (0.05 to 16.57) | Age of each risk and control interval | Self‐controlled case series |
36. Risk of bias summary: paralysis.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Arnheim‐Dahlström 2013‐DNK/SWE | Moderate | Low | Low | Low | Low | Low | Low | Moderate |
| Frisch 2018‐DNK | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Hviid 2017‐DNK/SWE | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Skufca 2018‐FIN | Serious | Low | Low | Low | Moderate | Moderate | Low | Serious |
| Yoon 2021‐KOR | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Study | Case definition | Case ascertainment independent? | Exposure | Co‐interventions | Observation period defined | Risk period defined | Comparability | Overall |
| Yoon 2021‐KOR | Yes, national database | Not reported | Yes, national database | Unclear | Yes, 466‐730 days post vaccine | Yes, 365 days post vaccine | Yes, adjusted for age | Low |
Five studies were included that reported on paralysis following HPV vaccination (Arnheim‐Dahlström 2013‐DNK/SWE; Frisch 2018‐DNK; Hviid 2017‐DNK/SWE; Skufca 2018‐FIN; Yoon 2021‐KOR). All five studies were retrospective cohort studies. One study also reported a self‐controlled case series analysis (Yoon 2021‐KOR).
In the short term, four cohort studies reported fewer cases of paralysis following HPV vaccination than no vaccine (RR 0.54, 95% CI 0.39 to 0.74; 4 studies, 19.8 million person‐years; I2 = 0%) (Analysis 2.4) (Arnheim‐Dahlström 2013‐DNK/SWE; Hviid 2017‐DNK/SWE; Skufca 2018‐FIN; Yoon 2021‐KOR). In the medium term, three studies also reported fewer cases of paralysis following HPV vaccination than no vaccine (RR 0.61, 95% CI 0.39 to 0.96; 3 studies, 17.7 million person‐years; I2 = 0%) (Hviid 2017‐DNK/SWE; Skufca 2018‐FIN; Yoon 2021‐KOR). In the long term, two studies reported no association between HPV vaccination and paralysis (RR 0.62, 95% CI 0.36 to 1.07; 2 studies, 20.7 million person‐years; I2 = 0%) (Analysis 2.4) (Frisch 2018‐DNK; Hviid 2017‐DNK/SWE).
2.4. Analysis.
Comparison 2: Specific adverse events, Outcome 4: Paralysis (cohort studies; short/medium/long‐term)
In a self‐controlled case series analysis (Yoon 2021‐KOR), there was no increased risk of paralysis following HPV vaccination (1 study, 33 cases of paralysis; RR 0.95, 95% CI 0.05 to 16.57) (Table 37).
Complex regional pain syndrome (CRPS)
See Table 39 for effect estimates and Table 40 for the risk of bias summary of included studies on CRPS. HPV vaccination likely does not increase the risk of CRPS (moderate‐certainty evidence; Table 2).
37. Specific adverse events effect estimates: complex regional pain syndrome (CRPS).
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 55,770 person‐years Unvaccinated: 244,158 person‐years |
Hazard ratio (short‐term) | 0.00 (0.00 to 0.00) | Hospital district, country background, number of hospital visits or admissions two years before vaccination | Cohort; no cases |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 186,946 person‐years Unvaccinated: 244,171 person‐years |
Hazard ratio (medium‐term) | 0.34 (0.11 to 1.05) | Hospital district, country background, number of hospital visits or admissions two years before vaccination | Cohort |
| Tsai 2023‐TWN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 15 years | Vaccinated: 494,660 person‐years Unvaccinated: 2,280,373 person‐years |
Standardised incidence ratio (short‐term) | 0.40 (‐0.73 to 1.54) | Unadjusted | Cohort |
| Tsai 2023‐TWN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 15 years | Vaccinated: 494,660 person‐years Unvaccinated: 2,280,373 person‐years |
Standardised incidence ratio (medium‐term) | 0.60 (‐0.82 to 2.02) | Unadjusted | Cohort |
| Vielot 2020‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 12 years | Vaccinated: 76,423 Unvaccinated: 47,558 |
Hazard ratio (immediate‐term) | 0.90 (0.46 to 1.73) | Physical trauma, infection, mental illness and use of primary care | Cohort |
| Vielot 2020‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 12 years | Vaccinated: 76,423 Unvaccinated: 47,558 |
Hazard ratio (short‐term) | 1.11 (0.83 to 1.47) | Physical trauma, infection, mental illness and use of primary care | Cohort |
| Vielot 2020‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 12 years | Vaccinated: 76,423 Unvaccinated: 47,558 |
Hazard ratio (long‐term) | 0.76 (0.62 to 0.94) | Physical trauma, infection, mental illness and use of primary care | Cohort |
| Hviid 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 27 years | Reference period: 486 cases Risk period: 49 cases |
Rate ratio (short‐term) | 1.31 (0.91 to 1.90) | Age, season | Self‐controlled case series |
38. Risk of bias summary: complex regional pain syndrome (CRPS).
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Skufca 2018‐FIN | Serious | Low | Low | Low | Moderate | Moderate | Low | Serious |
| Tsai 2023‐TWN | Serious | Serious | Low | Low | Moderate | Low | Low | Serious |
| Vielot 2020‐USA | Serious | Low | Moderate | Low | Low | Moderate | Low | Serious |
| Study | Case definition | Case ascertainment independent? | Exposure | Co‐interventions | Observation period defined | Risk period defined | Comparability | Overall |
| Hviid 2020‐DNK | Yes, ICD‐10 codes | Not reported | Yes, Danish vaccination register | Unclear | Yes, before and after risk period | Yes, 365 days post vaccine | Yes, adjusted for age and season | Low |
ICD‐10: International Statistical Classification of Diseases and Related Health Problems (10th Revision)
Four studies were included that reported on CRPS following HPV vaccination (Hviid 2020‐DNK; Skufca 2018‐FIN; Tsai 2023‐TWN; Vielot 2020‐USA). Three studies were retrospective cohort studies (Skufca 2018‐FIN; Tsai 2023‐TWN; Vielot 2020‐USA) and the third was a self‐controlled case series (Hviid 2020‐DNK).
In the immediate term (RR 0.90, 95% CI 0.46 to 1.75; 1 study, 123,981 females) to short term, there was no association between HPV vaccination and CRPS (RR 0.95, 95% CI 0.46 to 1.96; 2 studies, 123,981 females plus 2,775,033 person‐years) (Analysis 2.5). In the medium term, two studies reported no association between HPV vaccination and CRPS (RR 0.43, 95% CI 0.18 to 1.03; 2 studies, 3,206,150 person‐years) (Skufca 2018‐FIN; Tsai 2023‐TWN). In the long term, one study suggested that there was a reduced hazard of CRPS following HPV vaccination (HR 0.76, 95% CI 0.62 to 0.94; 1 study, 123,981 females) (Analysis 2.5) (Vielot 2020‐USA).
2.5. Analysis.
Comparison 2: Specific adverse events, Outcome 5: Complex regional pain syndrome (cohort studies; immediate/short/medium/long‐term)
In a self‐controlled case series analysis, there was no increase in the rate of CRPS following HPV vaccination (1 study, 535 cases of CRPS; IRR 1.31, 95% CI 0.91 to 1.90) (Hviid 2020‐DNK).
Guillain‐Barré syndrome
See Table 41 for effect estimates and Table 42 for the risk of bias summary of included studies on Guillain‐Barré syndrome. The evidence suggests that HPV vaccination does not increase the risk of Guillain‐Barré syndrome (low‐certainty evidence; Table 2).
39. Specific adverse events effect estimates: Guillain‐Barré syndrome (GBS).
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Arnheim‐Dahlström 2013‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 12 to 17 years | Vaccinated: 296,826 Unvaccinated: 700,759 |
Not estimable | ‐ | ‐ | Cohort; no cases in exposed group |
| Deceuninck 2018‐CAN | Gardasil (Merck quadrivalent) | Female and male, 9 to 17 years | Vaccinated: 558,995 Unvaccinated: 13,736,169 |
Risk ratio (long‐term) | 0.81 (0.29 to 2.26) | Sex, age, year of GBS diagnosis and H1N1 pandemic period | Cohort |
| Gronlund 2016‐SWE | Gardasil (Merck quadrivalent) | Female, 10 to 30 years* | Vaccinated: 7848 person‐years Unvaccinated: 245,807 person‐years |
Not estimable | ‐ | ‐ | Cohort; no cases in vaccinated group; *age at outcome |
| Hviid 2017‐DNK/SWE | Gardasil (Merck quadrivalent) | Female, 18 to 44 years* | Vaccinated: 319,298 person‐years Unvaccinated: 16,067,162 person‐years |
Not estimable | ‐ | ‐ | Cohort; no cases in vaccinated group; *age at outcome |
| Martin‐Merino 2021‐ESP | NR | Female, 9 to 28 years* | Vaccinated: 381,377 person‐years Unvaccinated: 1,029,655 person‐years |
Hazard ratio (long‐term) | 1.24 (0.19 to 8.00) | Region and antibiotic prescription | Cohort; *age at outcome |
| Miranda 2017‐FRA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Vaccinated: 678,765 person‐years Unvaccinated: 4,746,753 person‐years |
Hazard ratio (short‐term) | 3.94 (1.58 to 9.78) | Age, year of inclusion, geographical zone, CMUc, history of use of health care and other vaccinations, use of health care and other vaccinations after inclusion | Cohort |
| Miranda 2017‐FRA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Vaccinated: 1,393,228 person‐years Unvaccinated: 4,746,753 person‐years |
Hazard ratio (medium‐term) | 3.78 (1.79 to 7.98) | Age, year of inclusion, geographical zone, CMUc, history of use of health care and other vaccinations, use of health care and other vaccinations after inclusion | Cohort |
| Miranda 2017‐FRA | Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Vaccinated: 1,323,942 person‐years Unvaccinated: 4,746,753 person‐years |
Hazard ratio (medium‐term) | 3.78 (1.70 to 8.41) | Age, year of inclusion, geographical zone, CMUc, history of use of health care and other vaccinations, use of health care and other vaccinations after inclusion | Cohort |
| Miranda 2017‐FRA | Cervarix (GSK bivalent) | Female, 13 to 16 years | Vaccinated: 69,286 person‐years Unvaccinated: 4,746,753 person‐years |
Hazard ratio (medium‐term) | 8.08 (1.69 to 38.61) | Age, year of inclusion, geographical zone, CMUc, history of use of health care and other vaccinations, use of health care and other vaccinations after inclusion | Cohort |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 55,770 person‐years Unvaccinated: 244,141 person‐years |
Hazard ratio (short‐term) | 2.76 (0.24 to 32.04) | Hospital district, country background and number of any hospital visits or admissions two years before the scheduled vaccination | Cohort |
| Skufca 2018‐FIN | Cervarix (GSK bivalent) | Female, 11 to 15 years | Vaccinated: 186,946 person‐years Unvaccinated: 244,171 person‐years |
Hazard ratio (medium‐term) | 5.31 (0.62 to 45.39) | Hospital district, country background and number of any hospital visits or admissions two years before the scheduled vaccination | Cohort |
| Tsai 2023‐TWN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 15 years | V: 494,678 person‐years C: 2,280,368 person years |
Standardised incidence ratio (short‐term) | 0.21 (‐0.61 to 1.03) | Unadjusted | Cohort |
| Tsai 2023‐TWN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 15 years | V: 494,678 person‐years C: 2,280,368 person‐years |
Standardised incidence ratio (medium‐term) | 2.10 (‐0.97 to 5.17) | Unadjusted | Cohort |
| Willame 2016‐GBR | Cervarix (GSK bivalent) | Female, 9 to 24 years | Vaccinated: 64,705 person‐years Unvaccinated: 64,841 person‐years |
Not estimable | ‐ | ‐ | Cohort; no cases in vaccinated group |
| Yoon 2021‐KOR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 14 years | Vaccinated: 408,363 person‐years Unvaccinated: 60,626 person‐years |
Rate ratio (short‐term) | 0.13 (0.03 to 0.53) | Age, region of residence, type of health insurance, income level and anaemia | Cohort |
| Yoon 2021‐KOR | Cervarix (GSK bivalent) | Female, 11 to 14 years | Vaccinated: 93,272 person‐years Unvaccinated: 60,626 person‐years |
Not estimable | ‐ | ‐ | Cohort; no cases in vaccinated group |
| Yoon 2021‐KOR | Gardasil (Merck quadrivalent) | Female, 11 to 14 years | Vaccinated: 315,090 person‐years Unvaccinated: 60,626 person‐years |
Risk ratio (short‐term) | 0.17 (0.04 to 0.69) | Age, region of residence, type of health insurance, income level and anaemia | Cohort |
| Yoon 2021‐KOR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 14 years | Vaccinated: 790,069 person‐years Unvaccinated: 119,949 person‐years |
Rate ratio (medium‐term) | 0.19 (0.07 to 0.55) | Age, region of residence, type of health insurance, income level and anaemia | Cohort |
| Grimaldi‐Bensouda 2017‐FRA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 25 years* | Cases: 13 (0 vaccinated) Controls: 130 (2 vaccinated) |
Not estimable | ‐ | ‐ | Case‐control; no cases exposed to vaccine; *age at outcome |
| Andrews 2017‐GBR | Cervarix (GSK bivalent) | Female, 12 to 18 years | Reference period: 86 cases Risk period: 5 cases |
Relative incidence (short‐term) | 0.84 (0.30 to 2.34) | Age in years, period and season | Self‐controlled case series |
| Andrews 2017‐GBR | Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Reference period: 15 cases Risk period: 4 cases |
Relative incidence (short‐term) | 1.61 (0.39 to 6.64) | Age in years, period and season | Self‐controlled case series |
| Andrews 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Reference period: 101 cases Risk period: 9 cases |
Relative incidence (immediate‐term) | 1.04 (0.47 to 2.28) | Age in years, period and season | Self‐controlled case series |
| Andrews 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Reference period: 101 cases Risk period: 24 cases |
Relative incidence (short‐term) | 1.10 (0.57 to 2.14) | Age in years, period and season | Self‐controlled case series |
| Miranda 2017‐FRA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Reference period: 37 cases Risk period: 6 cases | Incidence rate ratio (immediate‐term) | 3.83 (1.67 to 8.75) | Age, A(H1N1) pandemics period and winter season Known for gastroenteritis/influenza‐like epidemics in France |
Self‐controlled case series; 42 days |
| Miranda 2017‐FRA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 13 to 16 years | Reference period: 32 cases Risk period: 11 cases | Incidence rate ratio (short‐term) | 2.39 (1.21 to 4.72) | Age, A(H1N1) pandemics period and winter season known for gastroenteritis/influenza‐like epidemics in France |
Self‐controlled case series; 6 months |
| Yoon 2021‐KOR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 14 years | Reference period: 7 cases Risk period: 5 cases |
Relative risk (short‐term) | 0.47 (0.02 to 9.36) | Age of each risk and control interval | Self‐controlled case series |
| Cameron 2016‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Pre‐vaccine: 220,810 Post‐vaccine: 206,323 |
Incidence rate ratio (long‐term; 2004 vs 2012) | 3.21 (0.13 to 78.8) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Cameron 2016‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Male, 12 to 18 years | Pre‐vaccine: 232,479 Post‐vaccine: 216,880 |
Incidence rate ratio (long‐term; 2004 vs 2012) | 1.07 (0.15 to 7.61) | Unadjusted | Pre‐ vs post‐vaccine introduction |
A(H1N1): influenza A virus subtype H1N1; CMUc: complementary Universal Health Insurance; GBS: Guillain‐Barré syndrome; NR: not reported
40. Risk of bias summary: Guillain‐Barre Syndrome (GBS).
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Arnheim‐Dahlström 2013‐DNK/SWE | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Deceuninck 2018‐CAN | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Gronlund 2016‐SWE | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Hviid 2017‐DNK/SWE | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Martin‐Merino 2021‐ESP | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Miranda 2017‐FRA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Skufca 2018‐FIN | Serious | Low | Low | Low | Moderate | Moderate | Low | Serious |
| Willame 2016‐GBR | Critical | Low | Low | Low | Low | Moderate | Low | Critical |
| Yoon 2021‐KOR | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Grimaldi‐Bensouda 2017‐FRA | Critical | Moderate | Low | Low | Low | Moderate | Low | Critical |
| Cameron 2016‐GBR | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Tsai 2023‐TWN | Serious | Serious | Low | Low | Moderate | Low | Low | Serious |
| Study | Case definition | Case ascertainment independent? | Exposure | Co‐interventions | Observation period defined | Risk period defined | Comparability | Overall |
| Andrews 2017‐GBR | Yes, hospital records | Not reported | Yes, GP records | Unclear | Yes, before and after risk period | Yes, 91 days post vaccine | Yes, adjusted for age and calendar time | Low |
| Miranda 2017‐FRA | Yes, insurance database | Not reported | Yes, insurance database | Unclear | No, limited methods reported | Yes, 42 days to 6 months post vaccine | Yes, adjusted for season and calendar time | Moderate |
| Yoon 2021‐KOR | Yes, national database | Not reported | Yes, national database | Unclear | Yes, 466 to 730 days post vaccine | Yes, 365 days post vaccine | Yes, adjusted for age | Low |
GP: general practitioner
Thirteen studies were included that reported on Guillain‐Barré syndrome following HPV vaccination (Andrews 2017‐GBR; Arnheim‐Dahlström 2013‐DNK/SWE; Cameron 2016‐GBR; Deceuninck 2018‐CAN; Grimaldi‐Bensouda 2017‐FRA; Gronlund 2016‐SWE; Hviid 2017‐DNK/SWE; Martin‐Merino 2021‐ESP; Miranda 2017‐FRA; Skufca 2018‐FIN; Tsai 2023‐TWN; Willame 2016‐GBR; Yoon 2021‐KOR). One study was a case‐control study (Grimaldi‐Bensouda 2017‐FRA), three were self‐controlled case series (Andrews 2017‐GBR; Miranda 2017‐FRA; Yoon 2021‐KOR), one reported pre‐ and post‐vaccine introduction rates (Cameron 2016‐GBR), and seven were cohort studies.
Four cohort studies each reported no cases of Guillain‐Barré syndrome in those exposed to HPV vaccination (Arnheim‐Dahlström 2013‐DNK/SWE; Gronlund 2016‐SWE; Hviid 2017‐DNK/SWE; Willame 2016‐GBR). In the short term, four cohort studies reported inconsistent results (Miranda 2017‐FRA; Skufca 2018‐FIN; Tsai 2023‐TWN; Yoon 2021‐KOR). One study from France reported a higher incidence of Guillain‐Barré syndrome following exposure to HPV vaccine (Miranda 2017‐FRA), while two studies reported no association (Skufca 2018‐FIN; Tsai 2023‐TWN) and a third study reported a negative association between HPV vaccine and Guillain‐Barré syndrome in the short term (Yoon 2021‐KOR). The pooled estimate indicated no difference between HPV vaccine and no vaccine in risk of Guillain‐Barré syndrome (RR 0.78, 95% CI 0.10 to 6.03; 4 studies, 8.2 million person‐years; I2 = 83%) (Analysis 2.6).
2.6. Analysis.
Comparison 2: Specific adverse events, Outcome 6: Guillain‐Barré syndrome (cohort studies; short/medium/long‐term)
In the medium term, four studies again reported inconsistent effects of HPV vaccination on Guillain‐Barré syndrome (RR 1.56, 95% CI 0.40 to 5.99; 4 studies, 9.5 million person‐years; I2 = 87%) (Analysis 2.6) (Miranda 2017‐FRA; Skufca 2018‐FIN; Tsai 2023‐TWN; Yoon 2021‐KOR).
In the long term, two studies indicated no difference between HPV vaccine and no vaccine in rates of Guillain‐Barré syndrome (RR 0.89, 95% CI 0.36 to 2.20; 2 studies, 15.7 million person‐years; I2 = 0%) (Analysis 2.6) (Deceuninck 2018‐CAN; Martin‐Merino 2021‐ESP).
Using a self‐controlled case series analysis, two studies reported no increased risk of Guillain‐Barré syndrome following HPV vaccination in the immediate term (RR 1.98, 95% CI 0.55 to 7.12; 2 studies, 153 cases; I2 = 80%) (Analysis 2.7) (Andrews 2017‐GBR; Miranda 2017‐FRA). In the short term, three studies reported no increased risk of Guillain‐Barré syndrome following HPV vaccination (RR 1.53, 95% CI 0.78 to 2.98; 3 studies, 180 cases; I2 = 37%) (Analysis 2.7)(Andrews 2017‐GBR; Miranda 2017‐FRA; Yoon 2021‐KOR).
2.7. Analysis.
Comparison 2: Specific adverse events, Outcome 7: Guillain‐Barré syndrome (self‐controlled case series)
One pre‐ versus post‐vaccine introduction study evaluated 12‐ to 18‐year‐old boys and girls from Great Britain (Cameron 2016‐GBR). There was no increase in the rates of Guillain‐Barré syndrome following the introduction of the HPV vaccine.
One case‐control study evaluated 11‐ to 25‐year‐old females (Grimaldi‐Bensouda 2017‐FRA). There were no cases of Guillain‐Barré syndrome in those exposed to HPV vaccine in this study.
Premature ovarian failure
See Table 43 for effect estimates and Table 44 for the risk of bias summary of included studies on premature ovarian failure. The evidence suggests that HPV vaccination does not increase the risk of premature ovarian failure (low‐certainty evidence; Table 2).
41. Specific adverse events effect estimates: premature ovarian failure.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Hviid 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 11 to 34 years | Vaccinated: 505,829 Unvaccinated: 490,471 |
Hazard ratio (long‐term) | 0.96 (0.55 to 1.68) | Calendar year, propensity score | Cohort |
| Hviid 2021‐DNK | Gardasil (Merck quadrivalent) | Female, vaccinated < 20 years old | Vaccinated: 333,505 Unvaccinated: 490,471 |
Hazard ratio (long‐term) | 0.77 (0.37 to 1.62) | Calendar year, propensity score | Cohort |
| Hviid 2021‐DNK | Gardasil (Merck quadrivalent) | Female, vaccinated ≥ 20 years old | Vaccinated: 505,829 Unvaccinated: 172,324 |
Hazard ratio (long‐term) | 1.15 (0.58 to 2.28) | Calendar year, propensity score | Cohort |
| Ter‐Minasyan 2024‐ARM | Gardasil (Merck quadrivalent) | Female, 15 to 24 years | Vaccinated: 39 Unvaccinated: 30 |
Odds ratio (short‐term) | 0.76 (0.05 to 12.72) | Unadjusted | Cohort |
| Ter‐Minasyan 2024‐ARM | Gardasil (Merck quadrivalent) | Female, 25 to 34 years | Vaccinated: 36 Unvaccinated: 30 |
Odds ratio (short‐term) | 0.83 (0.05 to 13.84) | Unadjusted | Cohort |
| Ter‐Minasyan 2024‐ARM | Gardasil (Merck quadrivalent) | Female, 35 to 40 years | Vaccinated: 23 Unvaccinated: 30 |
Odds ratio (short‐term) | 0.42 (0.02 to 10.75) | Unadjusted | Cohort |
| Tsai 2023‐TWN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 15 years | Vaccinated: 494,684 person‐years Unvaccinated: 2,280,280 person‐years |
Standardised incidence ratio (short‐term) | 0.27 (‐0.21 to 0.74) | Unadjusted | Cohort |
| Tsai 2023‐TWN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 15 years | Vaccinated: 494,684 person‐years Unvaccinated: 2,280,280 person‐years |
Standardised incidence ratio (medium‐term) | 0.91 (‐0.02 to 1.84) | Unadjusted | Cohort |
42. Risk of bias summary: premature ovarian failure.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Hviid 2021‐DNK | Moderate | Moderate | Low | Low | Low | Low | Low | Moderate |
| Ter‐Minasyan 2024‐ARM | Critical | Moderate | Serious | Low | Low | Serious | Moderate | Critical |
| Tsai 2023‐TWN | Critical | Low | Low | Low | Low | Low | Moderate | Critical |
Three retrospective cohort studies were included that reported on premature ovarian failure following HPV vaccination (Hviid 2021‐DNK; Ter‐Minasyan 2024‐ARM; Tsai 2023‐TWN).
Across the short term (RR 0.21, 95% CI 0.03 to 1.28; 2 studies, 128 females plus 2,774,964 person‐years; I2 = 29%), medium term (RR 0.91, 95% CI 0.55 to 1.51) and long term (RR 0.96, 95% CI 0.55 to 1.68) follow‐ups after HPV vaccination there was no association with premature ovarian failure (Analysis 2.8) (Table 43).
2.8. Analysis.
Comparison 2: Specific adverse events, Outcome 8: Premature ovarian failure (cohort studies; short/medium/long‐term)
Infertility
See Table 45 for effect estimates and Table 46 for the risk of bias summary of included studies on infertility. HPV vaccination likely does not increase the risk of infertility (moderate‐certainty evidence; Table 2).
43. Specific adverse events effect estimates: infertility.
| Study | Vaccine | Population (sex, age) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| McInerney 2017‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 32 years* | Vaccinated: 4932 Unvaccinated: 10332 |
Fecundability ratio (long‐term) | 0.98 (0.90 to 1.08) | Age at baseline, education, income, geographic region of residence, race/ethnicity, history of smoking, abnormal Pap test before age at vaccination and parent’s education | Cohort; *age at outcome |
| McInerney 2017‐USA | Gardasil (Merck quadrivalent) | Female, < 18 years | Vaccinated: 1094 Unvaccinated: 10332 |
Fecundability ratio (long‐term) | 1.00 (0.85 to 1.17) | Age at baseline, education, income, geographic region of residence, race/ethnicity, history of smoking, abnormal Pap test before age at vaccination and parent’s education | Cohort |
| McInerney 2017‐USA | Gardasil (Merck quadrivalent) | Female, ≥ 18 years | Vaccinated: 3842 Unvaccinated: 10332 |
Fecundability ratio (long‐term) | 0.98 (0.89 to 1.08) | Age at baseline, education, income, geographic region of residence, race/ethnicity, history of smoking, abnormal Pap test before age at vaccination and parent’s education | Cohort |
| McInerney 2017‐USA | Gardasil (Merck quadrivalent) | Male, 25 to 32 years* | Vaccinated: 211 Unvaccinated: 4177 |
Fecundability ratio (long‐term) | 1.07 (0.79 to 1.46) | Age at baseline, education, income, geographic region of residence, race/ethnicity, history of smoking | Cohort; *age at outcome |
| McInerney 2017‐USA | Gardasil (Merck quadrivalent) | Male, < 18 years old | Vaccinated: 48 Unvaccinated: 4177 |
Fecundability ratio (long‐term) | 1.10 (0.56 to 2.19) | Age at baseline, education, income, geographic region of residence, race/ethnicity, history of smoking | Cohort |
| McInerney 2017‐USA | Gardasil (Merck quadrivalent) | Male, ≥ 18 years | Vaccinated: 163 Unvaccinated: 4177 |
Fecundability ratio (long‐term) | 1.06 (0.75 to 1.50) | Age at baseline, education, income, geographic region of residence, race/ethnicity, history of smoking | Cohort |
| Schmuhl 2020‐USA | NR | Female, < 18 years old | NR | Odds ratio (long‐term) | 1.04 (0.22 to 4.97) | Body mass index, ever using birth control pills, any history of STI, health insurance status, routine access to health care, age, race/ethnicity, marriage, education and income | Cross‐sectional |
| Schmuhl 2020‐USA | NR | Female, ≥ 18 years | NR | Odds ratio (long‐term) | 0.42 (0.11 to 1.54) | Body mass index, ever using birth control pills, any history of STI, health insurance status, routine access to health care, age, race/ethnicity, marriage, education and income | Cross‐sectional |
NR: not reported; STI: sexually transmitted infection
44. Risk of bias summary: infertility.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| McInerney 2017‐USA | Moderate | Low | Moderate | Low | Serious | Moderate | Low | Serious |
| Schmuhl 2020‐USA | Serious | Low | Moderate | Low | Moderate | Moderate | Low | Serious |
Two studies were included that reported on infertility (not specified whether primary or secondary infertility) following HPV vaccination (McInerney 2017‐USA; Schmuhl 2020‐USA). One study was a retrospective cohort study (McInerney 2017‐USA) and the other was a cross‐sectional study (Schmuhl 2020‐USA).
The cohort study reported on fecundability (total number of pregnancies/total number of cycles) in 25‐ to 32‐year‐old women and their male partners in the USA (McInerney 2017‐USA). There was no association between HPV vaccine and fecundability in females receiving HPV vaccine before the age of 18 (fecundability ratio (FR) 1.0, 95% CI 0.85 to 1.17) or after the age of 18 (FR 0.98, 95% CI 0.89 to 1.08). For males, there was also no association between fecundability and those receiving HPV vaccine before 18 years of age (FR 1.1, 95% CI 0.56 to 2.19) or after 18 years of age (FR 1.06, 95% CI 0.75 to 1.50) (Table 45).
One study evaluated self‐reported infertility (not specified whether primary or secondary infertility) in 18‐ to 33‐year‐old women in the USA (Schmuhl 2020‐USA). There was no association between infertility and receiving HPV vaccine before the age of 18 (OR 1.04, 95% CI 0.22 to 4.97) or after the age of 18 (OR 0.42, 95% CI 0.11 to 1.54).
Sexual activity (measured by incidence of sexually transmitted infections)
See Table 47 for effect estimates and Table 48 for the risk of bias summary of included studies on sexual activity. HPV vaccination likely does not increase sexual activity (moderate‐certainty evidence; Table 2).
45. Specific adverse events effect estimates: sexual activity (measured by incidence of sexually transmitted infections).
| Study | Vaccine | Population (sex, age) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Bednarczyk 2012‐USA | Gardasil (Merck quadrivalent) | Female, 11 to 12 years | Vaccinated: 493 Unvaccinated: 905 |
Incidence rate ratio (medium‐term) | 0.68 (0.06 to 7.71) | Health care‐seeking behaviour in the previous year, age at vaccination, race and socioeconomic status | Cohort; chlamydia infection |
| Bednarczyk 2012‐USA | Gardasil (Merck quadrivalent) | Female, 11 to 12 years | Vaccinated: 493 Unvaccinated: 905 |
Incidence rate ratio (medium‐term) | 0.90 (0.09 to 9.07) | Health care‐seeking behaviour in the previous year, age at vaccination, race and socioeconomic status | Cohort; venereal disease, unspecified |
| Cummings 2012‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 17 years | Vaccinated: 75 Unvaccinated: 150 |
Odds ratio (medium‐term) | 0.9 (0.04 to 2.2) | Matched with two historical controls by age at enrolment, clinic site and reported sexual activity | Cohort; chlamydia infection |
| Cummings 2012‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 17 years | Vaccinated: 75 Unvaccinated: 150 |
Odds ratio (medium‐term) | ‐ | ‐ | Cohort; gonorrhoea (not estimable because no cases in vaccinated cohort) |
| Cummings 2012‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 17 years | Vaccinated: 75 Unvaccinated: 150 |
Odds ratio (medium‐term) | 5.3 (0.7 to 42.3) | Matched with two historical controls by age at enrolment, clinic site and reported sexual activity | Cohort; trichomonas |
| Sadler 2015‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Vaccinated: 231 Unvaccinated: 114 |
Odds ratio (medium‐term) | 1.18 (0.68 to 2.04) | Vaccine cohort | Cohort; received previous treatment for STI |
| Sadler 2015‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Vaccinated: 189 Unvaccinated: 81 |
Odds ratio (medium‐term) | 2.30 (1.06 to 5.00) | Vaccine cohort | Cohort; C trachomatis test positive |
| Jena 2015‐USA | Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Vaccinated: 21,610 Unvaccinated: 186,501 |
Difference‐in‐difference odds ratio (short‐term) | 1.05 (0.80 to 1.38) | Matched to non‐vaccinated females according to age, zip code of residence and health plan | Cross‐sectional; chlamydia, gonorrhoea, herpes, human immunodeficiency virus or AIDS, or syphilis |
| Sauvageau 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 11 to 18 years | Vaccinated: 1002 Unvaccinated: 473 |
Risk ratio (long‐term) | 0.63 (0.44 to 0.90) | Age, level of knowledge about STI and number of sexual partners during last 12 months | Cross‐sectional; diagnosis of a STI during last 12 months |
| Smith 2015‐CAN | Gardasil (Merck quadrivalent) | Female, 13 years | Pre‐vaccine: 131,781 Post‐vaccine: 128,712 |
Risk ratio (medium‐term) | 0.81 (0.63 to 1.04) | Neighbourhood income quintile, hepatitis B vaccination and history of sexual health‐related indicator and birth quarter | Pre‐ vs post‐vaccine introduction; non‐HPV STI |
Vaccinated: vaccinated; Unvaccinated: control
HPV: human papillomavirus; NR: not reported; SCCS: self‐controlled case series; STI: sexually transmitted infection
46. Risk of bias summary: sexual activity (measured by incidence of sexually transmitted infections).
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Bednarczyk 2012‐USA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Cummings 2012‐USA | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Sadler 2015‐GBR | Critical | Moderate | Moderate | Low | Moderate | Moderate | Low | Critical |
| Jena 2015‐USA | Serious | Low | Low | Low | No information | Low | Low | Serious |
| Sauvageau 2021‐CAN | Serious | Low | Serious | Low | Serious | Moderate | Low | Serious |
| Smith 2015‐CAN | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
Six studies were included that reported on sexual activity following HPV vaccination (Bednarczyk 2012‐USA; Cummings 2012‐USA; Jena 2015‐USA; Sadler 2015‐GBR; Sauvageau 2021‐CAN; Smith 2015‐CAN). This outcome was measured by the incidence of sexually transmitted infections (STI) in people who did and did not receive HPV vaccination.
All six studies reported on the incidence of STI, including chlamydia, venereal disease, gonorrhoea, herpes, HIV or AIDS, syphilis or trichomonas in females (Bednarczyk 2012‐USA; Cummings 2012‐USA; Jena 2015‐USA; Sadler 2015‐GBR; Sauvageau 2021‐CAN; Smith 2015‐CAN). There was no increase in the incidence of any STI following HPV vaccination. Two studies reported a decreased incidence of STIs following HPV vaccination (Sadler 2015‐GBR; Sauvageau 2021‐CAN).
One study reported on those receiving treatment for STIs in 14‐ to 20‐year‐old females (Sadler 2015‐GBR). There was no increase in the number receiving treatment for STIs following HPV vaccination.
Secondary clinical outcomes
Cervical screening attendance
See Table 49 for effect estimates and Table 50 for the risk of bias summary of included studies on cervical screening attendance.
47. Secondary clinical outcomes effect estimates: cervical screening attendance.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Ba 2021‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 21 to 26 years* | Vaccinated: 41,814 person years Unvaccinated: 46,320 person‐years |
Incidence rate ratio (long term; 3 doses) | 1.60 (1.58 to 1.63) | HPV vaccination status, age, place of residence, US census regions, type of health plan, flu vaccine, previous Pap, gonorrhoea, chlamydia, syphilis, trichomoniasis, HIV/AIDS, hepatitis B virus, hepatitis C virus, alcohol drinking, smoking, depression, anxiety and drug abuse | Cohort; *age at outcome |
| Ba 2021‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 21 to 26 years* | Vaccinated: 41,814 person‐years Unvaccinated: 811,553 person‐years |
Incidence rate ratio (long term; 2 doses) | 1.39 (1.37 to 1.41) | HPV vaccination status, age, place of residence, US census regions, type of health plan, flu vaccine, previous Pap, gonorrhoea, chlamydia, syphilis, trichomoniasis, HIV/AIDS, hepatitis B virus, hepatitis C virus, alcohol drinking, smoking, depression, anxiety and drug abuse | Cohort; *age at outcome |
| Ba 2021‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 21 to 26 years* | Vaccinated: 67,630 person‐years Unvaccinated: 811,553 person‐years |
Incidence rate ratio (long term; 1 dose) | 1.14 (1.13 to 1.16) | HPV vaccination status, age, place of residence, US census regions, type of health plan, flu vaccine, previous Pap, gonorrhoea, chlamydia, syphilis, trichomoniasis, HIV/AIDS, hepatitis B virus, hepatitis C virus, alcohol drinking, smoking, depression, anxiety and drug abuse | Cohort; *age at outcome |
| Badre‐Esfahani 2019‐DNK | NR | Female, 12 to 18 years | Vaccinated: 22,634 Unvaccinated: 2194 | Odds ratio (medium term) | 2.1 (1.9 to 2.3) | Parental civil status, highest parental education and occupation, family disposable income area of residence and country of origin | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 26 years | Vaccinated: 233 Unvaccinated: 1123 | Hazard ratio (long term; 3 doses) | 0.94 (0.71 to 1.26) | Age at study entry, age at initial screen and race | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 26 years | Vaccinated: 256 Unvaccinated: 1123 | Hazard ratio (long term; 2 doses) | 1.01 (0.77 to 1.34) | Age at study entry, age at initial screen and race | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 26 years | Vaccinated: 634 Unvaccinated: 1123 | Hazard ratio (long term; 1 dose) | 2.98 (2.45 to 3.61) | Age at study entry, age at initial screen and race | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 20 years | Vaccinated: 131 Unvaccinated: 398 | Hazard ratio (long term; 3 doses) | 1.15 (0.67 to 1.97) | Age at study entry, age at initial screen and race | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 20 years | Vaccinated: 90 Unvaccinated: 398 | Hazard ratio (long term; 2 doses) | 0.48 (0.25 to 0.90) | Age at study entry, age at initial screen and race | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 20 years | Vaccinated: 241 Unvaccinated: 398 | Hazard ratio (long term; 1 dose) | 1.65 (1.20 to 2.25) | Age at study entry, age at initial screen and race | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 21 to 26 years | Vaccinated: 118 Unvaccinated: 706 | Hazard ratio (long term; 3 doses) | 1.48 (1.09 to 2.01) | Age at study entry, age at initial screen and race | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 21 to 26 years | Vaccinated: 150 Unvaccinated: 706 | Hazard ratio (long term; 2 doses) | 1.53 (1.17 to 2.02) | Age at study entry, age at initial screen and race | Cohort |
| Boone 2016‐USA | Gardasil (Merck quadrivalent) | Female, 21 to 26 years | Vaccinated: 393 Unvaccinated: 706 | Hazard ratio (long term; 1 dose) | 2.38 (1.97 to 2.88) | Age at study entry, age at initial screen and race | Cohort |
| Del Mistro 2021‐ITA | Gardasil (Merck quadrivalent) | Female, 15 to 25 years | Vaccinated: 4718 Unvaccinated: 91,512 | Odds ratio (long term) | 1.07 (1.04 to 1.10) | Unadjusted | Cohort |
| Ruiz‐Sternberg 2014‐COL | NR | Female, < 26 years* | Vaccinated: 506 Unvaccinated: 930 | Odds ratio (NR) | 2.35 (1.69 to 3.28) | Educational level, knowledge and risk perception | Cohort; *age at outcome |
| Thamsborg 2020‐DNK | Gardasil (Merck quadrivalent) | Female, < 15 years | Vaccinated: 3983 Unvaccinated: 2148 | Risk ratio (long term) | 1.14 (1.08 to 1.22) | Unadjusted | Cohort |
| Thamsborg 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 15 years | Vaccinated: 17,901 Unvaccinated: 2148 | Risk ratio (long term) | 1.26 (1.19 to 1.33) | Unadjusted | Cohort |
| Thamsborg 2020‐DNK | Gardasil (Merck quadrivalent) | Female, > 15 years | Vaccinated: 823 Unvaccinated: 2148 | Risk ratio (long term) | 1.17 (1.08 to 1.26) | Unadjusted | Cohort |
| Yagi 2019‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 16 years | Vaccinated: 7389 Unvaccinated: 7872 | Risk ratio (long term) | 0.97 (0.88 to 1.06) | Unadjusted | Cohort |
| Sauvageau 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 11 to 18 years | Vaccinated: 1002 Unvaccinated: 473 | Risk ratio (NR) | 0.98 (0.90 to 1.07) | Age, ethnicity, use of contraception, having a family physician, level of knowledge about STI and number of sexual partners during life | Cross‐sectional |
| Taniguchi 2019‐JPN | NR | Female, 13 to 16 years | Vaccinated: 1753 Unvaccinated: 974 | Risk ratio (NR) | 1.60 (1.12 to 2.29) | Unadjusted | Cross‐sectional |
| Baldur‐Felskov 2014‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 26 years | Pre‐vaccine: 2,302,441 Post‐vaccine: 2,431,726 |
Rate ratio (long term; 2000 vs 2012) | 0.95 (0.95 to 0.95) | Unadjusted | Pre‐ vs post‐vaccine introduction |
HPV: human papillomavirus; NR: not reported; STI: sexually transmitted infection
48. Risk of bias summary: cervical screening attendance.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Ba 2021‐USA | Moderate | Low | Low | Low | Low | Low | Low | Moderate |
| Badre‐Esfahani 2019‐DNK | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Boone 2016‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Del Mistro 2021‐ITA | Critical | Low | Moderate | Low | Low | Low | Low | Critical |
| Ruiz‐Sternberg 2014‐COL | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Thamsborg 2020‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Sauvageau 2021‐CAN | Moderate | Low | Serious | Low | Serious | Serious | Low | Serious |
| Taniguchi 2019‐JPN | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Yagi 2019‐JPN | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Baldur‐Felskov 2014‐DNK | Critical | Low | Serious | Low | Low | Low | Low | Critical |
Ten studies were identified that reported on cervical screening attendance following HPV vaccination (Ba 2021‐USA; Badre‐Esfahani 2019‐DNK; Baldur‐Felskov 2014‐DNK; Boone 2016‐USA; Del Mistro 2021‐ITA; Ruiz‐Sternberg 2014‐COL; Sauvageau 2021‐CAN; Taniguchi 2019‐JPN; Thamsborg 2020‐DNK; Yagi 2019‐JPN).
Six were cohort studies (Ba 2021‐USA; Badre‐Esfahani 2019‐DNK; Boone 2016‐USA; Del Mistro 2021‐ITA; Ruiz‐Sternberg 2014‐COL; Thamsborg 2020‐DNK), three were cross‐sectional (Sauvageau 2021‐CAN; Taniguchi 2019‐JPN; Yagi 2019‐JPN), and one was a pre‐post vaccine introduction study (Baldur‐Felskov 2014‐DNK).
One cohort study reported an increased odds of cervical screening attendance in the medium term in those receiving HPV vaccination (OR 2.1, 95% CI 1.9 to 2.3; 1 cohort study, 24,828 females) (Badre‐Esfahani 2019‐DNK). From two of the cohort studies, the pooled estimate of the impact of HPV vaccination on rates of cervical screening attendance indicated an increase of 60% in the long term (RR 1.60, 95% CI 1.57 to 1.62; 2 cohort studies, 88,134 person‐years plus 1353 females; I2 = 0%) (Analysis 3.1). One additional cohort study reported an increased odds of cervical screening attendance in the long term in those receiving HPV vaccination (OR 2.35, 95% CI 1.69 to 3.28; 1 cohort study, 1436 females) (Ruiz‐Sternberg 2014‐COL).
3.1. Analysis.
Comparison 3: Secondary clinical outcomes, Outcome 1: Cervical screening attendance (cohort studies; long‐term)
Two cross‐sectional studies reported little to no difference in cervical screening attendance following HPV vaccination (Sauvageau 2021‐CAN; Yagi 2019‐JPN), while one reported an increased attendance (Taniguchi 2019‐JPN).
The pre‐post vaccine introduction study reported a decrease in cervical screening attendance between 2000 and 2012 (Baldur‐Felskov 2014‐DNK).
Two studies also reported on the effectiveness of two doses or one dose (Ba 2021‐USA; Boone 2016‐USA). Both indicated an increased likelihood of attending cervical screening following HPV vaccination with one or two doses.
Treatment for HPV‐related disease
See Table 51 for effect estimates and Table 52 for the risk of bias summary of included studies on treatment for HPV‐related disease.
49. Secondary clinical outcomes effect estimates: treatment rates.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Paraskevaidis 2020‐GRC | Gardasil (Merck quadrivalent) | Female, NR | Vaccinated: 849 Unvaccinated: 849 |
Risk ratio (NR) | 0.02 (0.00 to 0.11) | Unadjusted | Cohort; treatment needed for suspected high‐grade lesion |
| Elies 2022‐FRA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 19 to 30 years | Vaccinated: 4129 Unvaccinated: 38,323 |
Hazard ratio (long‐term) | 0.59 (0.39 to 0.90) | Unadjusted | Cohort; conisation rate |
| Clark 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 23 years* | Pre‐vaccine: 121,019 Post‐vaccine: 100,020 |
Incidence rate ratio (long‐term; 2003‐8 vs 2013‐18) | 0.24 (0.19 to 0.30) | Unadjusted | Pre‐ vs post‐vaccine introduction; trichloroacetic acid treatment; *age at outcome |
| Clark 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 23 years* | Pre‐vaccine: 121,019 Post‐vaccine: 100,020 |
Incidence rate ratio (long‐term; 2003‐8 vs 2013‐18) | 0.13 (0.10 to 0.17) | Unadjusted | Pre‐ vs post‐vaccine introduction; laser of vulval lesion; *age at outcome |
| Clark 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 23 years* | Pre‐vaccine: 121,019 Post‐vaccine: 100,020 |
Incidence rate ratio (long‐term; 2003‐8 vs 2013‐18) | 0.18 (0.13 to 0.24) | Unadjusted | Pre‐ vs post‐vaccine introduction; cervical conisation; *age at outcome |
| Clark 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 23 years* | Pre‐vaccine: 121,019 Post‐vaccine: 100,020 |
Incidence rate ratio (long‐term; 2003‐8 vs 2013‐18) | 0.14 (0.11 to 0.17) | Unadjusted | Pre‐ vs post‐vaccine introduction; loop electrosurgical excision procedure; *age at outcome |
| Clark 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 23 years* | Pre‐vaccine: 121,019 Post‐vaccine: 100,020 |
Incidence rate ratio (long‐term; 2003‐8 vs 2013‐18) | 0.17 (0.10 to 0.28) | Unadjusted | Pre‐ vs post‐vaccine introduction; cryotherapy; *age at outcome |
| Clark 2021‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 23 years* | Pre‐vaccine: 121,019 Post‐vaccine: 100,020 |
Incidence rate ratio (long‐term; 2003‐8 vs 2013‐18) | 0.51 (0.50 to 0.53) | Unadjusted | Pre‐ vs post‐vaccine introduction; colposcopy; *age at outcome |
| Cruickshank 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Pre‐vaccine: 1344 Post‐vaccine: 5669 |
Incidence rate ratio (long‐term; 2008‐9 vs 2009‐14) | 0.51 (0.41 to 0.66) | Unadjusted | Pre‐ vs post‐vaccine introduction; ablation (cold coagulation/cryotherapy) |
| Cruickshank 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 12 to 18 years | Pre‐vaccine: 1344 Post‐vaccine: 5669 |
Incidence rate ratio (long‐term; 2008‐9 vs 2009‐14) | 0.67 (0.58 to 0.79) | Unadjusted | Pre‐ vs post‐vaccine introduction; LLETZ/type‐3 excision |
| Harrison 2014‐AUS | Gardasil (Merck quadrivalent) | Female, 15 to 27 years* | N = 1,175,879 patient encounters | Risk ratio (medium‐term; 2002‐6 vs 2008‐12) | 0.39 (0.32 to 0.46) | Unadjusted | Pre‐ vs post‐vaccine introduction; genital warts management per 1000 patient encounters; *age at outcome |
| Harrison 2014‐AUS | Gardasil (Merck quadrivalent) | Female, 28 to 49 years* | N = 1,175,879 patient encounters | Risk ratio (long‐term; 2002‐6 vs 2008‐12) | 0.64 (0.48 to 0.85) | Unadjusted | Pre‐ vs post‐vaccine introduction; genital warts management per 1000 patient encounters; *age at outcome |
| Harrison 2014‐AUS | Gardasil (Merck quadrivalent) | Female, ≥ 50 years* | N = 1,175,879 patient encounters | Risk ratio (long‐term; 2002‐6 vs 2008‐12) | 1.00 (1.00 to 1.00) | Unadjusted | Pre‐ vs post‐vaccine introduction; genital warts management per 1000 patient encounters; *age at outcome |
| Harrison 2014‐AUS | Gardasil (Merck quadrivalent) | Male, 15 to 27 years* | N = 1,175,879 patient encounters | Risk ratio (medium‐term; 2002‐6 vs 2008‐12) | 0.95 (0.84 to 1.09) | Unadjusted | Pre‐ vs post‐vaccine introduction; genital warts management per 1000 patient encounters; *age at outcome |
| Harrison 2014‐AUS | Gardasil (Merck quadrivalent) | Male, 28 to 49 years* | N = 1,175,879 patient encounters | Risk ratio (long‐term; 2002‐6 vs 2008‐12) | 0.85 (0.70 to 1.03) | Unadjusted | Pre‐ vs post‐vaccine introduction; genital warts management per 1000 patient encounters; *age at outcome |
| Harrison 2014‐AUS | Gardasil (Merck quadrivalent) | Male, ≥ 50 years* | N = 1,175,879 patient encounters | Risk ratio (long‐term; 2002‐6 vs 2008‐12) | 0.78 (0.42 to 1.43) | Unadjusted | Pre‐ vs post‐vaccine introduction; genital warts management per 1000 patient encounters; *age at outcome |
LLETZ: large loop excision of the transformation zone; NR: not reported
50. Risk of bias summary: treatment rates.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Paraskevaidis 2020‐GRC | Serious | Serious | Serious | Low | Serious | Low | Low | Serious |
| Elies 2022‐FRA | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Clark 2021‐CAN | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Cruickshank 2017‐GBR | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Harrison 2014‐AUS | Critical | Low | Serious | Low | Low | Low | Low | Critical |
Five studies were identified that reported on treatment rates following HPV vaccination (Clark 2021‐CAN; Cruickshank 2017‐GBR; Elies 2022‐FRA; Harrison 2014‐AUS; Paraskevaidis 2020‐GRC). Two were cohort studies (Elies 2022‐FRA; Paraskevaidis 2020‐GRC) and three were pre‐post vaccine introduction studies (Clark 2021‐CAN; Cruickshank 2017‐GBR; Harrison 2014‐AUS).
One cohort study reported a decrease in conisation rates (HR 0.59, 95% 0.39 to 0.90) (Elies 2022‐FRA) and the other reported a decrease in treatment required for suspected high‐grade lesions (RR 0.02, 95% CI 0.00 to 0.11) following HPV vaccination (Paraskevaidis 2020‐GRC). Neither cohort study adjusted for confounding in the analysis.
One of the pre‐post vaccine introduction studies reported a decrease from 2003‐2008 to 2013‐2018 for trichloroacetic acid treatment, laser of vulval lesions, cervical conisation, loop electrosurgical excision procedure, cryotherapy and colposcopy (Clark 2021‐CAN). Another pre‐post vaccine introduction study reported a decrease from 2008‐2009 to 2009‐2014 for ablation (cold coagulation/cryotherapy) and loop electrosurgical excision procedure (Cruickshank 2017‐GBR). The third study reported a decrease in anogenital warts management between 2002‐2006 and 2008‐2012 for females ages 15 to 49 years (Harrison 2014‐AUS). For males, a decrease in treatment rates during this period was also reported, but confidence intervals included no difference.
Anogenital warts
See Table 53 and Table 54 for effect estimates and Table 55 for the risk of bias summary of included studies on anogenital warts. HPV vaccination probably reduces the incidence of anogenital warts (moderate‐certainty evidence; Table 1).
51. Secondary clinical outcomes effect estimates: anogenital warts (cohort studies).
| Study | Vaccine | Population (sex, age) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 14 years | Vaccinated: 134,908 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 1 dose) |
0.29 (0.22 to 0.38) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 15 to 16 years | Vaccinated: 23,106 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 1 dose) |
0.38 (0.29 to 0.49) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 17 to 18 years | Vaccinated: 8473 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 1 dose) |
0.56 (0.42 to 0.73) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, ≥ 19 years | Vaccinated: 69,166 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 1 dose) |
1.36 (1.24 to 1.49) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 14 years | Vaccinated: 269,786 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 2 doses) |
0.22 (0.18 to 0.26) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 15 to 16 years | Vaccinated: 50,448 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 2 doses) |
0.32 (0.26 to 0.38) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 17 to 18 years | Vaccinated: 13,290 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 2 doses) |
0.49 (0.39 to 0.62) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, ≥ 19 years | Vaccinated: 127,453 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 2 doses) |
1.03 (0.95 to 1.12) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 14 years | Vaccinated: 1,204,485 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 3 doses) |
0.16 (0.15 to 0.18) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 15 to 16 years | Vaccinated: 239,722 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 3 doses) |
0.20 (0.18 to 0.22) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, 17 to 18 years | Vaccinated: 72,162 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 3 doses) |
0.29 (0.25 to 0.33) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Baandrup 2021‐DNK | Gardasil (Merck quadrivalent) | Female, ≥ 19 years | Vaccinated: 418,219 person‐years Unvaccinated: 1,904,895 person‐years |
Incidence rate ratio (long‐term; 3 doses) |
0.76 (0.71 to 0.81) | Maternal highest achieved education, attained age, socioeconomic status, calendar time | Cohort |
| Cho 2024‐KOR | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 13 years* | Vaccinated: 166,031 Unvaccinated: 166,031 |
Hazard ratio (medium‐term) | 1.29 (0.57 to 2.94) | Birth year, socioeconomic status, regional urbanisation level | Cohort; *age at vaccination |
| Cho 2024‐KOR | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 12 to 13 years* | Vaccinated: 166,031 Unvaccinated: 166,031 |
Hazard ratio (long‐term) | 0.39 (0.28 to 0.52) | Birth year, socioeconomic status, regional urbanisation level | Cohort; *age at vaccination |
| Dominiak‐Felden 2015‐BEL | Gardasil (Merck quadrivalent) | Female, 10 to 23 years | Vaccinated: 116,379 person‐years Unvaccinated: 218,524 person‐years |
Risk ratio (long‐term; 3 doses) | 0.12 (0.07 to 0.26) | Age | Cohort |
| Dominiak‐Felden 2015‐BEL | Gardasil (Merck quadrivalent) | Female, 10 to 23 years | Vaccinated: 30,402 person‐years Unvaccinated: 218,524 person‐years |
Risk ratio (long‐term; 1 or 2 doses) | 0.50 (0.30 to 0.83) | Age | Cohort |
| Hariri 2018‐USA | Gardasil (Merck quadrivalent) | Female, 11 to 22 years | Vaccinated: 21,631 Unvaccinated: 31,563 |
Hazard ratio (long‐term; 3 doses) | 0.23 (0.17 to 0.31) | Race/ethnicity, health plan, age at enrolment in the health plan, age, age at first sexual activity, age at first dose of HPV vaccine, continuously enrolled, months enrolled in health plan, preventive health visits, Medicaid enrolment, oral contraceptive use, history of tests for pregnancy, chlamydia or gonorrhoea | Cohort |
| Hariri 2018‐USA | Gardasil (Merck quadrivalent) | Female, 11 to 22 years | Vaccinated: 2729 Unvaccinated: 31,563 |
Hazard ratio (long‐term; 2 doses) | 0.32 (0.17 to 0.59) | Race/ethnicity, health plan, age at enrolment in the health plan, age, age at first sexual activity, age at first dose of HPV vaccine, continuously enrolled, months enrolled in health plan, preventive health visits, Medicaid enrolment, oral contraceptive use, history of tests for pregnancy, chlamydia or gonorrhoea | Cohort |
| Hariri 2018‐USA | Gardasil (Merck quadrivalent) | Female, 11 to 22 years | Vaccinated: 5864 Unvaccinated: 31,563 |
Hazard ratio (long‐term; 1 dose) | 0.81 (0.60 to 1.08) | Race/ethnicity, health plan, age at enrolment in the health plan, age, age at first sexual activity, age at first dose of HPV vaccine, continuously enrolled, months enrolled in health plan, preventive health visits, Medicaid enrolment, oral contraceptive use, history of tests for pregnancy, chlamydia or gonorrhoea | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 10 to 16 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 3 doses) | 0.18 (0.15 to 0.22) | Age and parental education level | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 17 to 19 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 3 doses) | 0.23 (0.18 to 0.29) | Age and parental education level | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 10 to 19 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 3 doses) | 0.20 (0.17 to 0.23) | Age and parental education level | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 10 to 16 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 2 doses) | 0.29 (0.21 to 0.40) | Age and parental education level | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 17 to 19 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 2 doses) | 0.35 (0.26 to 0.47) | Age and parental education level | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 10 to 19 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 2 doses) | 0.32 (0.26 to 0.40) | Age and parental education level | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 10 to 16 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 1 dose) | 0.31 (0.20 to 0.49) | Age and parental education level | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 17 to 19 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 1 dose) | 0.71 (0.55 to 0.92) | Age and parental education level | Cohort |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 10 to 19 years | N = 1,045,165 | Incidence rate ratio (medium‐term; 1 dose) | 0.54 (0.43 to 0.68) | Age and parental education level | Cohort |
| Howell‐Jones 2013‐GBR | Cervarix (GSK bivalent) | Female, 15 years* | N = 1,212,679 | Incidence rate ratio (medium‐term) | 0.83 (0.73 to 0.95) | Chlamydia diagnosis rate | Cohort; *age at outcome |
| Howell‐Jones 2013‐GBR | Cervarix (GSK bivalent) | Female, 16 years* | N = 1,247,309 | Incidence rate ratio (medium‐term) | 0.81 (0.73 to 0.89) | Chlamydia diagnosis rate | Cohort; *age at outcome |
| Howell‐Jones 2013‐GBR | Cervarix (GSK bivalent) | Female, 17 years* | N = 1,278,085 | Incidence rate ratio (medium‐term) | 0.69 (0.62 to 0.76) | Chlamydia diagnosis rate | Cohort; *age at outcome |
| Howell‐Jones 2013‐GBR | Cervarix (GSK bivalent) | Female, 18 years* | N = 1,314,995 | Incidence rate ratio (medium‐term) | 0.73 (0.65 to 0.83) | Chlamydia diagnosis rate | Cohort; *age at outcome |
| Howell‐Jones 2013‐GBR | Cervarix (GSK bivalent) | Female, 19 years* | N = 1,344,061 | Incidence rate ratio (long‐term) | 0.97 (0.86 to 1.09) | Chlamydia diagnosis rate | Cohort; *age at outcome |
| Howell‐Jones 2013‐GBR | Cervarix (GSK bivalent) | Female, 20 years* | N = 1,358,690 | Incidence rate ratio (long‐term) | 0.90 (0.74 to 1.10) | Chlamydia diagnosis rate | Cohort; *age at outcome |
| Munoz‐Quiles 2021‐ESP | Gardasil (Merck quadrivalent) | Female, 14 years | Vaccinated: 53,579 Unvaccinated: 290,708 |
Risk ratio (long‐term; 3 doses) | 0.26 (0.21 to 0.32) | Age, calendar year, health department, immunocompromising conditions | Cohort |
| Munoz‐Quiles 2021‐ESP | Gardasil (Merck quadrivalent) | Female, 14 years | Vaccinated: 3526 Unvaccinated: 290,708 |
Risk ratio (long‐term; 2 doses) | 0.40 (0.22 to 0.65) | Age, calendar year, health department, immunocompromising conditions | Cohort |
| Munoz‐Quiles 2021‐ESP | Gardasil (Merck quadrivalent) | Female, 14 years | Vaccinated: 1823 Unvaccinated: 290,708 |
Risk ratio (long‐term; 1 dose) | 0.25 (0.08 to 0.56) | Age, calendar year, health department, immunocompromising conditions | Cohort |
| Nygard 2023‐NOR | Gardasil (Merck quadrivalent) | Female, ≤ 13 at vaccination | Vaccinated: 174,506 Unvaccinated: 869,289 |
Hazard ratio (long‐term) | 0.2 (0.2 to 0.3) | Age, vaccination status, vaccination age, calendar time | Cohort |
| Nygard 2023‐NOR | Gardasil (Merck quadrivalent) | Female, 14 to 15 at vaccination | Vaccinated: 11,039* Unvaccinated: 869,289 |
Hazard ratio (long‐term) | 0.2 (0.2 to 0.3) | Age, vaccination status, vaccination age, calendar time | Cohort; *total vaccinated 14‐19 years |
| Nygard 2023‐NOR | Gardasil (Merck quadrivalent) | Female, 16 to 17 at vaccination | Vaccinated: 11,039* Unvaccinated: 869,289 |
Hazard ratio (long‐term) | 0.3 (0.2 to 0.3) | Age, vaccination status, vaccination age, calendar time | Cohort; *total vaccinated 14‐19 years |
| Nygard 2023‐NOR | Gardasil (Merck quadrivalent) | Female, 18 to 19 at vaccination | Vaccinated: 11,039* Unvaccinated: 869,289 |
Hazard ratio (long‐term) | 0.5 (0.4 to 0.7) | Age, vaccination status, vaccination age, calendar time | Cohort; *total vaccinated 14‐19 years |
| Nygard 2023‐NOR | Gardasil (Merck quadrivalent) | Female, 20 to 24 at vaccination | Vaccinated: 3320 Unvaccinated: 869,289 |
Hazard ratio (long‐term) | 1.0 (0.8 to 1.4) | Age, vaccination status, vaccination age, calendar time | Cohort |
| Nygard 2023‐NOR | Gardasil (Merck quadrivalent) | Female, 25 to 29 at vaccination | Vaccinated: 2725 Unvaccinated: 869,289 |
Hazard ratio (long‐term) | 1.3 (0.8 to 2.2) | Age, vaccination status, vaccination age, calendar time | Cohort |
| Nygard 2023‐NOR | Gardasil (Merck quadrivalent) | Female, 30+ at vaccination | Vaccinated: 1160 Unvaccinated: 869,289 |
Hazard ratio (long‐term) | 2.7 (1.1 to 6.6) | Age, vaccination status, vaccination age, calendar time | Cohort |
| Osmani 2022‐DEU | Gardasil (Merck quadrivalent); Cervarix (GSK bivalent); Gardasil 9 (Merck nonavalent) | Female, 19 to 28 years | Vaccinated: 121,337 Unvaccinated: 218,953 |
Hazard ratio (long‐term) | 0.37 (0.34 to 0.40) | Place of residence, type of vaccine, contraception use | Cohort |
| Perkins 2017‐USA | Gardasil (Merck quadrivalent) | Female, 9 to 25 years | Vaccinated: 185,973 Unvaccinated: 201,933 |
Incidence rate ratio (long‐term) | 0.52 (0.60 to 0.46) | Age, geographic region, income, proportion of minorities in county of residence, calendar year | Cohort |
| Reyburn 2023‐FJI | Gardasil (Merck quadrivalent) | Female, 15 to 23 years | Vaccinated: 189 Unvaccinated: 376 |
Prevalence ratio (3 doses; long‐term) | 1.28 (0.37 to 4.48) | Age, ethnicity and smoking | Cohort |
| Reyburn 2023‐FJI | Gardasil (Merck quadrivalent) | Female, 15 to 23 years | Vaccinated: 99 Unvaccinated: 376 |
Prevalence ratio (2 doses; long‐term) | 0.61 (0.08 to 4.95) | Age, ethnicity and smoking | Cohort |
| Reyburn 2023‐FJI | Gardasil (Merck quadrivalent) | Female, 15 to 23 years | Vaccinated: 158 Unvaccinated: 376 |
Prevalence ratio (1 dose; long‐term) | 0.37 (0.05 to 2.95) | Age, ethnicity and smoking | Cohort |
| Swedish 2013‐USA | Gardasil (Merck quadrivalent) | Male, 26 to 76 years* | Vaccinated: 116 Unvaccinated: 197 |
Hazard ratio (medium‐term) | 0.45 (0.22 to 0.92) | Age, anogenital condyloma within 5 years prior to study entry, oncogenic HPV infection | Cohort; *age at outcome |
| Willows 2018‐CAN | Gardasil (Merck quadrivalent) | Female, 9 to 18 years | Vaccinated: 3521 Unvaccinated: 94,327 |
Hazard ratio (long‐term; 1 dose) | 0.6 (0.2 to 1.8) | Birth date, area of residence, previous hospitalisation, previous physician visit | Cohort |
| Willows 2018‐CAN | Gardasil (Merck quadrivalent) | Female, 9 to 18 years | Vaccinated: 6666 Unvaccinated: 94,327 |
Hazard ratio (long‐term; 2 doses) | 1.4 (0.6 to 3.3) | Birth date, area of residence, previous hospitalisation, previous physician visit | Cohort |
| Willows 2018‐CAN | Gardasil (Merck quadrivalent) | Female, 9 to 18 years | Vaccinated: 21,277 Unvaccinated: 94,327 |
Hazard ratio (long‐term; 3 doses) | 0.4 (0.3 to 0.7) | Birth date, area of residence, previous hospitalisation, previous physician visit | Cohort |
| Woestenberg 2020‐NLD | Cervarix (GSK bivalent) | Female, 12 to 16 years | Vaccinated: 154,088 person‐years Unvaccinated: 144,129 person‐years |
Incidence rate ratio (long‐term; 3 doses) | 0.72 (0.61 to 0.86) | Age as time‐varying, migration background, educational level, fear of STI/HIV consultations, mean number of GP consultations per year | Cohort |
| Woestenberg 2020‐NLD | Cervarix (GSK bivalent) | Female, 12 to 16 years | Vaccinated: 26,409 person‐years Unvaccinated: 144,129 person‐years |
Incidence rate ratio (long‐term; 1 or 2 doses) | 0.96 (0.68 to 1.32) | Age as time‐varying, migration background, educational level, fear of STI/HIV consultations, mean number of GP consultations per year | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 9 to 14 years | Vaccinated: 16,844 Unvaccinated: 94,233 |
Hazard ratio (long‐term; 1 dose) | 0.80 (0.34 to 1.90) | Sex, region, history of STI | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 9 to 14 years | Vaccinated: 17,090 Unvaccinated: 94,233 |
Hazard ratio (long‐term; 2 doses) | 1.36 (0.65 to 2.86) | Sex, region, history of STI | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 9 to 14 years | Vaccinated: 60,299 Unvaccinated: 94,233 |
Hazard ratio (long‐term; 3 doses) | 0.78 (0.46 to 1.35) | Sex, region, history of STI | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 15 to 19 years | Vaccinated: 26,543 Unvaccinated: 141,662 |
Hazard ratio (long‐term; 1 dose) | 0.65 (0.49 to 0.85) | Sex, region, history of STI | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 15 to 19 years | Vaccinated: 27,884 Unvaccinated: 141,662 |
Hazard ratio (long‐term; 2 doses) | 0.67 (0.51 to 0.89) | Sex, region, history of STI | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 15 to 19 years | Vaccinated: 87,235 Unvaccinated: 141,662 |
Hazard ratio (long‐term; 3 doses) | 0.58 (0.49 to 0.70) | Sex, region, history of STI | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 20 to 26 years | Vaccinated: 10,893 Unvaccinated: 51,068 |
Hazard ratio (long‐term; 1 dose) | 0.96 (0.72 to 1.28) | Sex, region, history of STI | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 20 to 26 years | Vaccinated: 10,658 Unvaccinated: 51,068 |
Hazard ratio (long‐term; 2 doses) | 1.15 (0.87 to 1.51) | Sex, region, history of STI | Cohort |
| Zeybek 2018‐USA | Gardasil (Merck quadrivalent) | Female and male, 20 to 26 years | Vaccinated: 29,517 Unvaccinated: 51,068 |
Hazard ratio (long‐term; 3 doses) | 1.11 (0.91 to 1.35) | Sex, region, history of STI | Cohort |
GP: general practitioner; HPV: human papillomavirus; STI: sexually transmitted infection
52. Secondary clinical outcomes effect estimates: anogenital warts (other study designs).
| Study | Vaccine | Population (sex, age) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Krasnopolsky 2020‐RUS | NR | Female, 18 to 36 years* | Vaccinated: 320 Unvaccinated: 120 |
Risk ratio (medium‐term) | 0.00 (0.00 to 0.02) | Unadjusted | Cross‐sectional; *age at outcome; no cases in exposed group |
| Petras 2015‐CZE | Gardasil (Merck quadrivalent) | Female, 16 to 40 years | Vaccinated: 882 Unvaccinated: 17,344 |
Odds ratio (long‐term; 3 doses) | 0.12 (0.05 to 0.25) | Age | Cross‐sectional |
| Petras 2015‐CZE | Cervarix (GSK bivalent) | Female, 16 to 40 years | Vaccinated: 633 Unvaccinated: 17,344 |
Odds ratio (long‐term; 3 doses) | 1.18 (0.86 to 1.63) | Age | Cross‐sectional |
| Petras 2015‐CZE | Gardasil (Merck quadrivalent) | Female, 16 to 40 years | Vaccinated: 1086 Unvaccinated: 17,344 |
Odds ratio (long‐term; at least 1 dose) | 0.09 (0.04 to 0.20) | Age | Cross‐sectional |
| Petras 2015‐CZE | Cervarix (GSK bivalent) | Female, 16 to 40 years | Vaccinated: 769 Unvaccinated: 17,344 |
Odds ratio (long‐term; at least 1 dose) | 1.10 (0.82 to 1.49) | Age | Cross‐sectional |
| Sadler 2015‐GBR | NR | Female, 12 to 18 years | Vaccinated: 231 Unvaccinated: 132 |
Odds ratio (medium‐term) | 0.66 (0.34 to 1.31) | Vaccine cohort | Cross‐sectional |
| Ali 2013‐AUS | Gardasil (Merck quadrivalent) | Female, 15 to 24 years* | 6950 cases of AGW | Rate ratio (medium‐term; 2000‐7 vs 2007‐11) | 0.33 (0.30 to 0.37) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome; vulval/vaginal warts |
| Ali 2013‐AUS | Gardasil (Merck quadrivalent) | Female, 25 to 34 years* | 6950 cases of AGW | Rate ratio (long‐term; 2000‐7 vs 2007‐11) | 0.60 (0.54 to 0.66) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome; vulval/vaginal warts |
| Ali 2013‐AUS | Gardasil (Merck quadrivalent) | Male, 15 to 24 years* | 6950 cases of AGW | Rate ratio (medium‐term; 2000‐7 vs 2007‐11) | 0.76 (0.62 to 0.96) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome; penile warts |
| Ali 2013‐AUS | Gardasil (Merck quadrivalent) | Male, 25 to 34 years* | 6950 cases of AGW | Rate ratio (long‐term; 2000‐7 vs 2007‐11) | 0.81 (0.66 to 0.99) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome; penile warts |
| Ali 2013‐AUS | Gardasil (Merck quadrivalent) | Male, 15 to 24 years* | 6950 cases of AGW | Rate ratio (medium‐term; 2000‐7 vs 2007‐11) | 0.92 (0.77 to 1.10) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome; anal warts |
| Ali 2013‐AUS | Gardasil (Merck quadrivalent) | Male, 25 to 34 years* | 6950 cases of AGW | Rate ratio (long‐term; 2000‐7 vs 2007‐11) | 0.69 (0.59 to 0.79) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome; anal warts |
| Bauer 2012‐USA | Gardasil (Merck quadrivalent) | Female, all ages* | Pre‐vaccine: 1,679,684 person‐years Post‐vaccine: 1,813,222 person‐years |
Incidence rate ratio (medium‐term; 2007 vs 2010 | 0.88 (0.86 to 0.90) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Bauer 2012‐USA | Gardasil (Merck quadrivalent) | Male, all ages* | Pre‐vaccine: 232,032 person‐years Post‐vaccine: 290,456 person‐years |
Incidence rate ratio (medium‐term; 2007 vs 2010 | 0.93 (0.90 to 0.96) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Canvin 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 15 to 19 years* | NR | Incidence rate ratio (medium‐term; 2009 vs 2010‐2014) | 0.69 (0.67 to 0.72) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Canvin 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | NR | Incidence rate ratio (medium‐term; 2009 vs 2010‐2014) | 0.91 (0.87 to 0.94) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Canvin 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Male, 15 to 19 years* | NR | Incidence rate ratio (medium‐term; 2009 vs 2010‐2014) | 0.75 (0.70 to 0.79) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Canvin 2017‐GBR | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Male, 20 to 24 years* | NR | Incidence rate ratio (medium‐term; 2009 vs 2010‐2014) | 0.88 (0.85 to 0.91) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Chow 2021b‐AUS | Gardasil (Merck quadrivalent) | Female, ≥ 15 years* | Pre‐vaccine: 35,137 Post‐vaccine: 81,204 |
Prevalence ratio (long‐term; 2004‐7 vs 2013‐18 | 0.42 (0.40 to 0.44) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Chow 2021b‐AUS | Gardasil (Merck quadrivalent) | Male, ≥ 15 years* | Pre‐vaccine: 32,022 Post‐vaccine: 30,343 |
Prevalence ratio (long‐term; 2004‐7 vs 2013‐18 | 0.55 (0.53 to 0.57) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Chow 2019‐AUS | Gardasil (Merck quadrivalent) | Male, ≤ 15 years* | Pre‐vaccine: 152 Post‐vaccine: 146 |
Prevalence ratio (medium‐term; 2014‐15 vs 2016‐17) | 0.15 (0.00 to 1.16) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Cocchio 2017‐ITA | Gardasil (Merck quadrivalent) | Male, ≥ 12 years* | 6076 cases of AGW | Annual percent change (medium‐term; 2004‐7 vs 2008‐15) | 3.8% (1.2% to 6.4%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Cocchio 2017‐ITA | Gardasil (Merck quadrivalent) | Female, ≥ 12 years* | 6076 cases of AGW | Annual percent change (medium‐term; 2004‐7 vs 2008‐15) | ‐6.1% (‐8.4% to ‐3.7%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Dominiak‐Felden 2015‐BEL | Gardasil (Merck quadrivalent) | Female, 10 to 23 years | Pre‐vaccine: 907,047 Post‐vaccine: 1,284,493 |
Incidence rate ratio (long‐term; 2006 vs 2009‐13) | 0.28 (0.22 to 0.35) | Age and gender | Pre‐ vs post‐vaccine introduction |
| Fernandes 2021‐PRT | Gardasil (Merck quadrivalent) | Female, ≤ 19 years* | NR | Relative change (medium‐term; 2008 vs 2017) | ‐86.8% | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Fernandes 2021‐PRT | Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | NR | Relative change (long‐term; 2008 vs 2017) | ‐77.4% | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Fernandes 2021‐PRT | Gardasil (Merck quadrivalent) | Male, ≤ 19 years* | NR | Relative change (medium‐term; 2008 vs 2017) | ‐38.5% | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Fernandes 2021‐PRT | Gardasil (Merck quadrivalent) | Male, 20 to 24 years* | NR | Relative change (long‐term; 2008 vs 2017) | ‐19.3% | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Flagg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 39 years | 88,911,951 person‐years | Annual percent change (medium‐term; 2006 vs 2009) | 5.6% (‐3.8% to 16.0%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Flagg 2018‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 39 years | 88,911,951 person‐years | Annual percent change (medium‐term; 2009 vs 2014) | ‐6.2% (‐9.0% to ‐3.3%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Flagg 2018‐USA | Gardasil (Merck quadrivalent) | Male, 15 to 39 years | 88,911,951 person‐years | Annual percent change (medium‐term; 2006 vs 2009) | 16.5% (8.7% to 24.8%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Flagg 2018‐USA | Gardasil (Merck quadrivalent) | Male, 15 to 39 years | 88,911,951 person‐years | Annual percent change (medium‐term; 2009 vs 2014) | 2.4% (0.5% to 4.3%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Goodman 2024‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) |
Female, 28 to 33 years* | N = 61,520 | Relative risk (long‐term) | 0.60 (0.46 to 0.79) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Guerra 2016‐CAN | Gardasil (Merck quadrivalent) | Females, 12 to 13 years | NR | Incidence rate ratio (long‐term; 2004 vs 2013) | 1.02 (0.78 to 1.33) | Pap‐test rate | Pre‐ vs post‐vaccine introduction |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 15 to 19 years* | NR | Annual percent change (long‐term; 2006‐7 vs 2010‐12) | 2006‐7: 2.8% (‐5.5% to 11.8%) 2010‐12: ‐18.6% (‐22.8% to ‐14.1%) |
Calendar year, sex and 5‐year age categories | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | NR | Annual percent change (long‐term; 2006‐7 vs 2010‐12) | 2006‐7: 0.4% (‐3.5% to 4.4%) 2010‐12: ‐11.3% (‐13.5% to ‐9.1%) |
Calendar year, sex and 5‐year age categories | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Female, 25 to 29 years* | NR | Annual percent change (long‐term; 2006‐7 vs 2010‐12) | 2006‐7: ‐4.2% (‐5.0% to ‐3.4%) 2010‐12: ‐4.2% (‐5.0% to ‐3.4%) |
Calendar year, sex and 5‐year age categories | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Male, 15 to 19 years* | NR | Annual percent change (long‐term; 2006‐7 vs 2010‐12) | 2006‐7: 6.6% (2.4% to 10.9%) 2010‐12: ‐16.6% (‐21.7% to ‐11.1%) |
Calendar year, sex and 5‐year age categories | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Male, 20 to 24 years* | NR | Annual percent change (long‐term; 2006‐7 vs 2010‐12) | 2006‐7: ‐0.7% (‐2.1% to 0.6%) 2010‐12: ‐11.0% (‐14.3% to ‐7.6%) |
Calendar year, sex and 5‐year age categories | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Herweijer 2018‐SWE | Gardasil (Merck quadrivalent) | Male, 25 to 29 years* | NR | Annual percent change (long‐term; 2006‐7 vs 2010‐12) | 2006‐7: 0.5% (‐2.1% to 3.2%) 2010‐12: ‐7.0% (‐13.2% to ‐0.4%) |
Calendar year, sex and 5‐year age categories | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Judlin 2016‐FRA | Gardasil (Merck quadrivalent) | Female, 15 to 26 years | Pre‐vaccine: 39,190 Post‐vaccine: 45,628 |
Incidence rate ratio (medium‐term; 2008‐9 vs 2011‐12) | 1.12 (0.91 to 1.37) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Kury 2013‐BRA | Gardasil (Merck quadrivalent) | Female, 12 to 20 years | NR | Incidence rate ratio (long‐term; 2007 vs 2012) | 0.50 (0.25 to 0.96) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Liu 2014‐AUS | Gardasil (Merck quadrivalent) | Female, 18 to 39 years* | Pre‐vaccine: 4862 Post‐vaccine: 2363 |
Odds ratio (long‐term; 2001 vs 2011) | 1.10 (0.78 to 1.54) | Age, place of residence, country of birth, Aboriginal or Torres Strait Islander status, education level, self‐reporting of chlamydia | Pre‐ vs post‐vaccine introduction, *age at outcome |
| Lukac 2020‐CAN | Gardasil (Merck quadrivalent) | Female and male, 20 to 28 years* | N = 85,158 | Relative risk (long‐term; birth cohort 1994‐6 vs 1991‐3) | 0.44 (0.34 to 0.59) | Age and period | Pre‐ vs post‐vaccine introduction, *age at outcome |
| Lurie 2017‐ISR | Gardasil (Merck quadrivalent) | Female, 9 to 45 years | Pre‐vaccine: 293,240 Post‐vaccine: 323,436 |
Odds ratio (medium‐term; 2006 vs 2015) | 0.48 (0.38 to 0.60) | Unadjusted | Pre‐ vs post‐vaccine introduction; ≤ 18 at outcome |
| Lurie 2017‐ISR | Gardasil (Merck quadrivalent) | Female, 9 to 45 years | Pre‐vaccine: 143,955 Post‐vaccine: 133,917 |
Odds ratio (long‐term; 2006 vs 2015) | 0.75 (0.71 to 0.80) | Unadjusted | Pre‐ vs post‐vaccine introduction; 25 to 34 at outcome |
| Lurie 2017‐ISR | Gardasil (Merck quadrivalent) | Male, 9 to 45 years | Pre‐vaccine: 310,339 Post‐vaccine: 342,190 |
Odds ratio (medium‐term; 2006 vs 2015) | 0.59 (0.45 to 0.77) | Unadjusted | Pre‐ vs post‐vaccine introduction; ≤ 18 at outcome |
| Lurie 2017‐ISR | Gardasil (Merck quadrivalent) | Male, 9 to 45 years | Pre‐vaccine: 123,476 Post‐vaccine: 125,751 |
Odds ratio (long‐term; 2006 vs 2015) | 0.96 (0.91 to 1.01) | Unadjusted | Pre‐ vs post‐vaccine introduction; 25 to 34 at outcome |
| Mann 2019‐USA | Gardasil (Merck quadrivalent) | Male, all ages | Pre‐vaccine: 96,243 Post‐vaccine: 185,844 |
Annual percent change (long‐term; 2010 vs 2016) | ‐8.1% (‐10.4% to ‐6.1%) | Jurisdiction | Pre‐ vs post‐vaccine introduction |
| Naleway 2020‐USA | Gardasil (Merck quadrivalent) | Female, 11 to 26 years | N = 565,356 | Incidence rate ratio (long‐term; 2000‐6 vs 2007‐16) | 0.69 (0.65 to 0.75) | Baseline level and trend in AGW incidence | Pre‐ vs post‐vaccine introduction |
| Naleway 2020‐USA | Gardasil (Merck quadrivalent) | Male, 11 to 21 years | N = 565,356 | Incidence rate ratio (long‐term; 2000‐10 vs 2011‐16) | 0.90 (0.84 to 0.97) | Baseline level and trend in AGW incidence | Pre‐ vs post‐vaccine introduction |
| Nsouli‐Maktabi 2013‐USA | Gardasil (Merck quadrivalent) | Female, NR | Pre‐vaccine: 1,544,029 Post‐vaccine: 1,440,362 |
Incidence rate ratio (long‐term; 2005 vs 2012) | 0.83 (0.82 to 0.85) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Nsouli‐Maktabi 2013‐USA | Gardasil (Merck quadrivalent) | Male, NR | Pre‐vaccine: 1,544,029 Post‐vaccine: 1,440,362 |
Incidence rate ratio (long‐term; 2005 vs 2012) | 1.37 (1.34 to 1.39) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Oliphant 2011‐NZL | Gardasil (Merck quadrivalent) | Female and male, 11 to 20 years | Pre‐vaccine: 21,739 Post‐vaccine: 19,054 |
Incidence rate ratio (medium‐term; 2007 vs 2010) | 0.82 (0.77 to 0.89) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Orumaa 2020‐NOR/DNK | Gardasil (Merck quadrivalent) | Female, 12 to 26 years | Pre‐vaccine: 693,534 Post‐vaccine: 789,550 |
Annual percent change (long‐term; 2009 vs 2015) | ‐4.8% (‐5.3% to ‐4.3%) | Age‐standardised | Pre‐ vs post‐vaccine introduction; Norway |
| Orumaa 2020‐NOR/DNK | Gardasil (Merck quadrivalent) | Male, 12 to 26 years | Pre‐vaccine: 830,930 Post‐vaccine: 724,268 |
Annual percent change (long‐term; 2009 vs 2015) | ‐1.9% (‐2.4% to ‐1.4%) | Age‐standardised | Pre‐ vs post‐vaccine introduction; Norway |
| Orumaa 2020‐NOR/DNK | Gardasil (Merck quadrivalent) | Female, 12 to 26 years | Pre‐vaccine: 817,222 Post‐vaccine: 801,125 |
Annual percent change (long‐term; 2009 vs 2015) | ‐18.0% (‐18.6% to ‐17.5%) | Age‐standardised | Pre‐ vs post‐vaccine introduction; Denmark |
| Orumaa 2020‐NOR/DNK | Gardasil (Merck quadrivalent) | Male, 12 to 26 years | Pre‐vaccine: 848,038 Post‐vaccine: 824,729 |
Annual percent change (long‐term; 2009 vs 2015) | ‐10.7% (‐11.2% to ‐10.3%) | Age‐standardised | Pre‐ vs post‐vaccine introduction; Denmark |
| Perkins 2015‐USA | Gardasil (Merck quadrivalent) | Female, 16 to 26 years | Pre‐vaccine: 32,834 Post‐vaccine: 33,007 |
Diagnosis rate trend (long‐term; 2011‐2013) | ‐22.1% | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Perkins 2015‐USA | Gardasil (Merck quadrivalent) | Male, 16 to 26 years | Pre‐vaccine: 32,834 Post‐vaccine: 33,007 |
Diagnosis rate trend (long‐term; 2011‐2013) | ‐13.5% | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Restivo 2023‐ITA | NR | Female and male, age NR | N = 59,449 cases | Rate ratio (2008 vs 2018) | 0.67 (0.50 to 0.89) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Sando 2014‐DNK | Gardasil (Merck quadrivalent) | Female, 15 to 19 years* | Pre‐vaccine: 164,754 Post‐vaccine: 173,448 |
Incidence rate ratio (medium‐term; 2008 vs 2011) | 0.31 (0.29 to 0.34) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Sando 2014‐DNK | Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | Pre‐vaccine: 150,760 Post‐vaccine: 166,608 |
Incidence rate ratio (long‐term; 2008 vs 2011) | 0.83 (0.79 to 0.87) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Sando 2014‐DNK | Gardasil (Merck quadrivalent) | Female, 25 to 29 years* | Pre‐vaccine: 157,405 Post‐vaccine: 155,686 |
Incidence rate ratio (long‐term; 2008 vs 2011) | 1.03 (0.96 to 1.10) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Sando 2014‐DNK | Gardasil (Merck quadrivalent) | Female, 30 to 34 years* | Pre‐vaccine: 181,587 Post‐vaccine: 167,953 |
Incidence rate ratio (long‐term; 2008 vs 2011) | 0.98 (0.89 to 1.07) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Shing 2019‐USA | Gardasil (Merck quadrivalent) | Female, 15 to 19 years* | Pre‐vaccine: 303,825 person‐years Post‐vaccine: 2,461,739 person‐years |
Annual percent change (long‐term; 2006 vs 2014) | ‐10.6% (‐12.6% to ‐8.5%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Shing 2019‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | Pre‐vaccine: 303,825 person‐years Post‐vaccine: 2,461,739 person‐years |
Annual percent change (long‐term; 2006 vs 2014) | ‐3.9% (‐7.1% to ‐0.6%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Shing 2019‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years* | Pre‐vaccine: 303,825 person‐years Post‐vaccine: 2,461,739 person‐years |
Annual percent change (long‐term; 2006 vs 2014) | 5.2% (0.3% to 10.3%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Shing 2019‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 39 years* | Pre‐vaccine: 303,825 person‐years Post‐vaccine: 2,461,739 person‐years |
Annual percent change (long‐term; 2006 vs 2014) | 6.5% (‐4.7% to 18.9%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Shing 2019‐USA | Gardasil (Merck quadrivalent) | Male, 15 to 19 years* | Pre‐vaccine: 303,825 person‐years Post‐vaccine: 2,461,739 person‐years |
Annual percent change (long‐term; 2006 vs 2014) | 4.4% (‐11.4% to 22.9%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Shing 2019‐USA | Gardasil (Merck quadrivalent) | Male, 20 to 24 years* | Pre‐vaccine: 303,825 person‐years Post‐vaccine: 2,461,739 person‐years |
Annual percent change (long‐term; 2006 vs 2014) | 5.9% (‐0.4% to 12.6%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Shing 2019‐USA | Gardasil (Merck quadrivalent) | Male, 25 to 29 years* | Pre‐vaccine: 303,825 person‐years Post‐vaccine: 2,461,739 person‐years |
Annual percent change (long‐term; 2006 vs 2014) | 10.0% (5.7% to 14.6%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Shing 2019‐USA | Gardasil (Merck quadrivalent) | Male, 30 to 39 years* | Pre‐vaccine: 303,825 person‐years Post‐vaccine: 2,461,739 person‐years |
Annual percent change (long‐term; 2006 vs 2014) | 4.1% (‐3.1% to 11.9%) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Smith 2016‐AUS | Gardasil (Merck quadrivalent) | Female, 12 to 69 years | Pre‐vaccine: 18,751 Post‐vaccine: 6060 |
Incidence rate ratio (long‐term; 1999‐2008 vs 2007‐2011 | 0.59 (0.48 to 0.73) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Smith 2016‐AUS | Gardasil (Merck quadrivalent) | Male, 12 to 69 years | Pre‐vaccine: 18,751 Post‐vaccine: 6060 |
Incidence rate ratio (long‐term; 1999‐2008 vs 2007‐2011 | 0.90 (0.69 to 1.17) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Sonnenberg 2019‐GBR | Cervarix (GSK bivalent) | Female, 16 to 44 years* | Vaccinated: 5257 Unvaccinated: 5869 |
Prevalence ratio (long‐term; 1999‐2001 vs 2010‐2012 | 1.10 (0.71 to 1.71) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Sonnenberg 2019‐GBR | Cervarix (GSK bivalent) | Male, 16 to 44 years* | Vaccinated: 3570 Unvaccinated: 4267 |
Prevalence ratio (long‐term; 1999‐2001 vs 2010‐2012 | 1.02 (0.64 to 1.66) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Steben 2018‐CAN | Gardasil (Merck quadrivalent) | Female, 9 to 17 years | Pre‐vaccine: 11,098 Post‐vaccine: 10,313 |
Incidence rate ratio (long‐term; 2004‐7 vs 2009‐12) | 0.82 (0.74 to 0.92) | Age | Pre‐ vs post‐vaccine introduction |
| Steben 2018‐CAN | Gardasil (Merck quadrivalent) | Male, 9 to 17 years | Pre‐vaccine: 11,098 Post‐vaccine: 10,313 |
Incidence rate ratio (long‐term; 2004‐7 vs 2009‐12) | 0.95 (0.86 to 1.04) | Age | Pre‐ vs post‐vaccine introduction |
| Thompson 2016‐CAN | Gardasil (Merck quadrivalent) | Female, 11 to 12 years | NR | Odds ratio (long‐term; 1990‐94 vs 2010‐11) | 0.77 (0.72 to 0.82) | Age group, geographic residential area category and income quintile | Pre‐ vs post‐vaccine introduction |
| Thompson 2016‐CAN | Gardasil (Merck quadrivalent) | Male, NR | NR | Odds ratio (long‐term; 1990‐94 vs 2010‐11) | 1.24 (1.17 to 2.01) | Age group, geographic residential area category and income quintile | Pre‐ vs post‐vaccine introduction |
| Thöne 2017‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Male, 11 to 79 years* | Pre‐vaccine: 4,370,000 person‐years Post‐vaccine: 2,330,000 person‐years |
Incidence rate ratio (medium‐term; 2005 vs 2010) | 1.18 (1.07 to 1.24) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
| Thöne 2017‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 11 to 79 years* | Pre‐vaccine: 2,040,000 person‐years Post‐vaccine: 2,680,000 person‐years |
Incidence rate ratio (medium‐term; 2005 vs 2010) | 0.88 (0.83 to 0.94) | Unadjusted | Pre‐ vs post‐vaccine introduction; *age at outcome |
AGW: anogenital warts; NR: not reported
53. Risk of bias summary: anogenital warts.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Baandrup 2021‐DNK | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Cho 2024‐KOR | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Dominiak‐Felden 2015‐BEL | Serious | Moderate | Low | Low | Moderate | Moderate | Moderate | Serious |
| Hariri 2018‐USA | Moderate | Low | Low | Low | Low | Low | Low | Moderate |
| Herweijer 2018‐SWE | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Howell‐Jones 2013‐GBR | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Munoz‐Quiles 2021‐ESP | Serious | Low | Low | Low | Low | Low | Serious | Serious |
| Nygard 2023‐NOR | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Osmani 2022‐DEU | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Perkins 2017‐USA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Reyburn 2023‐FJI | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Swedish 2013‐USA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Willows 2018‐CAN | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Woestenberg 2020‐NLD | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Zeybek 2018‐USA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Krasnopolsky 2020‐RUS | Critical | Critical | Low | Moderate | Low | Low | Low | Critical |
| Petras 2015‐CZE | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Sadler 2015‐GBR | Critical | Moderate | Moderate | Low | Moderate | Moderate | Low | Critical |
| Ali 2013‐AUS | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Bauer 2012‐USA | Critical | Serious | Serious | Moderate | Moderate | Low | Low | Critical |
| Canvin 2017‐GBR | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Chow 2021b‐AUS | Critical | Moderate | Serious | Low | Moderate | Low | Low | Critical |
| Chow 2019‐AUS | Critical | Serious | Serious | Moderate | Low | Low | Low | Critical |
| Cocchio 2017‐ITA | Serious | Serious | Serious | Moderate | Low | Low | Moderate | Serious |
| Dominiak‐Felden 2015‐BEL | Serious | Moderate | Low | Low | Moderate | Moderate | Moderate | Serious |
| Fernandes 2021‐PRT | Critical | Moderate | Serious | Moderate | Low | Low | Low | Critical |
| Flagg 2018‐USA | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Goodman 2024‐DEU | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Guerra 2016‐CAN | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Herweijer 2018‐SWE | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Judlin 2016‐FRA | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Kury 2013‐BRA | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Liu 2014‐AUS | Serious | Low | Serious | Low | Low | Low | Low | Serious |
| Lukac 2020‐CAN | Serious | Low | Low | Low | Low | Low | Moderate | Serious |
| Lurie 2017‐ISR | Critical | Serious | Serious | Low | Low | Serious | Moderate | Critical |
| Mann 2019‐USA | Serious | Moderate | Serious | Low | Low | Low | Serious | Serious |
| Naleway 2020‐USA | Serious | Low | Serious | Low | Low | Low | Moderate | Serious |
| Nsouli‐Maktabi 2013‐USA | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Oliphant 2011‐NZL | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Orumaa 2020‐NOR/DNK | Serious | Low | Serious | Low | Low | Low | Low | Serious |
| Perkins 2015‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Restivo 2023‐ITA | Critical | Serious | Serious | Low | Low | Low | Low | Critical |
| Sando 2014‐DNK | Serious | Low | Serious | Low | Moderate | Low | Low | Serious |
| Shing 2019‐USA | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Smith 2016‐AUS | Critical | Serious | Serious | Low | Low | Low | Low | Critical |
| Sonnenberg 2019‐GBR | Critical | Low | Serious | Low | Moderate | Moderate | Low | Critical |
| Steben 2018‐CAN | Critical | Serious | Serious | Low | Low | Low | Low | Critical |
| Thompson 2016‐CAN | Serious | Low | Serious | Low | Low | Low | Low | Serious |
| Thöne 2017‐DEU | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
Forty‐seven studies were identified that reported on anogenital warts following HPV vaccination (Ali 2013‐AUS; Baandrup 2021‐DNK; Bauer 2012‐USA; Canvin 2017‐GBR; Cho 2024‐KOR; Chow 2019‐AUS; Chow 2021b‐AUS; Cocchio 2017‐ITA; Dominiak‐Felden 2015‐BEL; Fernandes 2021‐PRT; Flagg 2018‐USA; Goodman 2024‐DEU; Guerra 2016‐CAN; Hariri 2018‐USA; Herweijer 2018‐SWE; Howell‐Jones 2013‐GBR; Judlin 2016‐FRA; Krasnopolsky 2020‐RUS; Kury 2013‐BRA; Liu 2014‐AUS; Lukac 2020‐CAN; Lurie 2017‐ISR; Mann 2019‐USA; Munoz‐Quiles 2021‐ESP; Naleway 2020‐USA; Nsouli‐Maktabi 2013‐USA; Nygard 2023‐NOR; Oliphant 2011‐NZL; Orumaa 2020‐NOR/DNK; Osmani 2022‐DEU; Perkins 2015‐USA; Perkins 2017‐USA; Petras 2015‐CZE; Restivo 2023‐ITA; Reyburn 2023‐FJI; Sadler 2015‐GBR; Sando 2014‐DNK; Shing 2019‐USA; Smith 2016‐AUS; Sonnenberg 2019‐GBR; Steben 2018‐CAN; Swedish 2013‐USA; Thompson 2016‐CAN; Thöne 2017‐DEU; Willows 2018‐CAN; Woestenberg 2020‐NLD; Zeybek 2018‐USA).
Fifteen were cohort studies (Baandrup 2021‐DNK; Cho 2024‐KOR; Dominiak‐Felden 2015‐BEL; Hariri 2018‐USA; Herweijer 2018‐SWE; Howell‐Jones 2013‐GBR; Munoz‐Quiles 2021‐ESP; Nygard 2023‐NOR; Osmani 2022‐DEU; Perkins 2017‐USA; Reyburn 2023‐FJI; Swedish 2013‐USA; Willows 2018‐CAN; Woestenberg 2020‐NLD; Zeybek 2018‐USA), three were cross‐sectional (Krasnopolsky 2020‐RUS; Petras 2015‐CZE; Sadler 2015‐GBR), and 29 were pre‐post vaccine introduction studies (Ali 2013‐AUS; Bauer 2012‐USA; Canvin 2017‐GBR; Chow 2021b‐AUS; Chow 2019‐AUS; Cocchio 2017‐ITA; Fernandes 2021‐PRT; Flagg 2018‐USA; Goodman 2024‐DEU; Guerra 2016‐CAN; Judlin 2016‐FRA; Kury 2013‐BRA; Liu 2014‐AUS; Lukac 2020‐CAN; Lurie 2017‐ISR; Mann 2019‐USA; Naleway 2020‐USA; Nsouli‐Maktabi 2013‐USA; Oliphant 2011‐NZL; Orumaa 2020‐NOR/DNK; Perkins 2015‐USA; Restivo 2023‐ITA; Sando 2014‐DNK; Shing 2019‐USA; Smith 2016‐AUS; Sonnenberg 2019‐GBR; Steben 2018‐CAN; Thompson 2016‐CAN; Thöne 2017‐DEU). Two of the cohort studies also reported incidence over time using the pre‐post vaccine introduction design (Dominiak‐Felden 2015‐BEL; Herweijer 2018‐SWE).
From the cohort studies, the pooled estimate of the impact of HPV vaccination on rates of anogenital warts indicated a reduction of 47% in the medium term (RR 0.53, 95% CI 0.37 to 0.77; 4 studies, 6,430,295 females and 313 males; I2 = 98%) (Analysis 3.2) and 53% in the long term (RR 0.47, 95% CI 0.36 to 0.61; 13 studies, 4.5 million person‐years plus 5,802,969 females and males; I2 = 99%) (Analysis 3.2). An analysis restricted to those receiving an HPV vaccine at or before the age of 16 years showed a reduction of anogenital warts incidence of 40% in the medium term (RR 0.60, 95% CI 0.30 to 1.21; 3 studies, 3,837,215 females; I2 = 99%) and 70% in the long term (RR 0.30, 95% CI 0.20 to 0.43; 6 studies, 3,647,319 person‐years plus 1,874,676 females and males; I2 = 97%) (Analysis 3.3).
3.2. Analysis.
Comparison 3: Secondary clinical outcomes, Outcome 2: Anogenital warts (cohort studies; medium/long‐term)
3.3. Analysis.
Comparison 3: Secondary clinical outcomes, Outcome 3: Anogenital warts (cohort studies; medium/long‐term; ≤ 16 years at vaccination)
Of the three cross‐sectional studies (Krasnopolsky 2020‐RUS; Petras 2015‐CZE; Sadler 2015‐GBR), one did not report any cases of anogenital warts in the HPV vaccine‐exposed group (Krasnopolsky 2020‐RUS). The other two studies reported a decreased risk of anogenital warts following HPV vaccination, but with confidence intervals that included no difference.
Of the 31 pre‐post vaccine introduction studies, seven reported only on females (Dominiak‐Felden 2015‐BEL; Goodman 2024‐DEU; Guerra 2016‐CAN; Judlin 2016‐FRA; Kury 2013‐BRA; Liu 2014‐AUS; Sando 2014‐DNK), two reported only on males (Chow 2019‐AUS; Mann 2019‐USA), and 22 reported on both (Ali 2013‐AUS; Bauer 2012‐USA; Canvin 2017‐GBR; Chow 2021b‐AUS; Cocchio 2017‐ITA; Fernandes 2021‐PRT; Flagg 2018‐USA; Herweijer 2018‐SWE; Lukac 2020‐CAN; Lurie 2017‐ISR; Naleway 2020‐USA; Nsouli‐Maktabi 2013‐USA; Oliphant 2011‐NZL; Orumaa 2020‐NOR/DNK; Perkins 2015‐USA; Restivo 2023‐ITA; Shing 2019‐USA; Smith 2016‐AUS; Sonnenberg 2019‐GBR; Steben 2018‐CAN; Thompson 2016‐CAN; Thöne 2017‐DEU).
In females, 23 studies (79%) reported a decrease in anogenital warts incidence over time and 6 (22%) reported either an increase or a decrease, but with confidence intervals that included no difference. In males, 12 studies (52%) reported a decrease in anogenital warts incidence over time and 11 (48%) reported either an increase or a decrease, but with confidence intervals that included no difference.
Eight cohort studies (Baandrup 2021‐DNK; Dominiak‐Felden 2015‐BEL; Hariri 2018‐USA; Herweijer 2018‐SWE; Munoz‐Quiles 2021‐ESP; Willows 2018‐CAN; Woestenberg 2020‐NLD; Zeybek 2018‐USA) and one cross‐sectional study (Petras 2015‐CZE) reported on the effectiveness of two doses or one dose of HPV vaccine. Six of the cohort studies reported a reduction in anogenital warts following two doses of HPV vaccine, though the effectiveness appeared to vary depending on age at vaccination (Baandrup 2021‐DNK; Dominiak‐Felden 2015‐BEL; Hariri 2018‐USA; Herweijer 2018‐SWE; Munoz‐Quiles 2021‐ESP; Zeybek 2018‐USA). Four of the studies also reported a reduction in anogenital warts following one dose of HPV vaccine (Baandrup 2021‐DNK; Herweijer 2018‐SWE; Munoz‐Quiles 2021‐ESP; Zeybek 2018‐USA).
Pregnancy and neonatal outcomes
See Table 56 for effect estimates and Table 57 for the risk of bias summary of included studies on pregnancy and neonatal outcomes.
54. Secondary clinical outcomes effect estimates: pregnancy and neonatal outcomes.
| Study | Vaccine | Population (sex, age) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Baril 2015‐GBR | Cervarix (GSK bivalent) | Female, 14 to 23 years | Vaccinated: 207 Unvaccinated: 632 |
Hazard ratio (short‐term) | 1.34 (0.81 to 2.24) | Age at first day of gestation, smoking, alcohol consumption, gestation start during the H1N1 pandemic season, general practice region, diabetes and high blood pressure during pregnancy, number of previous pregnancies, vaccination with another vaccine from −90 to +90 days gestation, and use of contraindicated drugs during the first trimester of gestation | Cohort; spontaneous abortion during the first 23 weeks of gestation |
| Baril 2015‐GBR | Cervarix (GSK bivalent) | Female, 14 to 23 years | Vaccinated: 207 Unvaccinated: 632 |
Odds ratio (short‐term) | 2.29 (0.51 to 10.32) | Unadjusted | Cohort; stillbirth |
| Baril 2015‐GBR | Cervarix (GSK bivalent) | Female, 14 to 23 years | Vaccinated: 207 Unvaccinated: 632 |
Odds ratio (short‐term) | 0.67 (0.28 to 1.67) | Unadjusted | Cohort; preterm delivery |
| Baril 2015‐GBR | Cervarix (GSK bivalent) | Female, 14 to 23 years | Vaccinated: 207 Unvaccinated: 632 |
Odds ratio (short‐term) | 0.89 (0,29 to 2.71) | Age at first day of gestation | Cohort; major birth defects |
| Bukowinski 2020‐USA | Gardasil (Merck quadrivalent) | Female, 17 to 28 years | Vaccinated: 1775 Unvaccinated: 88,825 |
Hazard ratio (short‐term) | 1.05 (0.94 to 1.18) | Maternal age, race/ethnicity, military rank, marital status, receipt of vaccines not routinely recommended in pregnancy and receipt of prenatal care | Cohort; spontaneous abortion |
| Bukowinski 2020‐USA | Gardasil (Merck quadrivalent) | Female, 17 to 28 years | Vaccinated: 1775 Unvaccinated: 88,825 |
Hazard ratio (short‐term) | 0.92 (0.76 to 1.13) | Maternal age, race/ethnicity, military rank, marital status, receipt of vaccines not routinely recommended in pregnancy and receipt of prenatal care | Cohort; preterm labour/delivery |
| Bukowinski 2020‐USA | Gardasil (Merck quadrivalent) | Female, 17 to 28 years | Vaccinated: 1775 Unvaccinated: 88,825 |
Relative risk (short‐term) | 0.67 (0.47 to 0.96) | Maternal age, race/ethnicity, military rank, marital status, receipt of vaccines not routinely recommended in pregnancy and receipt of prenatal care | Cohort; any structural birth defect |
| Faber 2019‐DNK | Gardasil (Merck quadrivalent) | Female, 14 to 39 years | Vaccinated: 5160 Unvaccinated: 309,010 |
Odds ratio (short‐term) | 0.96 (0.57 to 1.61) | Age at conception, education, smoking and BMI | Cohort; stillbirth |
| Faber 2019‐DNK | Gardasil (Merck quadrivalent) | Female, 14 to 39 years | Vaccinated: 5145 Unvaccinated: 308,062 |
Hazard ratio (short‐term) | 0.94 (0.53 to 1.67) | Age at conception, education, smoking and BMI | Cohort; infant mortality |
| Faber 2019‐DNK | Gardasil (Merck quadrivalent) | Female, 14 to 39 years | Vaccinated: 6710 Unvaccinated: 466,883 |
Rate ratio (short‐term) | 1.08 (0.87 to 1.34) | Age at conception, birth year of the woman, education, marital status, ethnicity, number of previous births, number of previous spontaneous and induced abortions, history of genital warts, chlamydia and pelvic inflammatory disease | Cohort; spontaneous abortion within the first 7 weeks |
| Scheller 2017‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 27 years | Vaccinated: 1665 Unvaccinated: 6660 |
Prevalence odds ratio (short‐term) | 1.19 (0.90 to 1.58) | Matched on age, calendar year of pregnancy onset and propensity score (age at pregnancy onset, place of birth, married or living with partner, level of education, household income, pregnancy history, smoking, body mass index, medical history, health care utilisation | Cohort; major birth defect |
| Scheller 2017‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 27 years | Vaccinated: 463 Unvaccinated: 1852 |
Hazard ratio (short‐term) | 0.71 (0.45 to 1.14) | Matched on age, calendar year of pregnancy onset and propensity score (age at pregnancy onset, place of birth, married or living with partner, level of education, household income, pregnancy history, smoking, body mass index, medical history, health care utilisation | Cohort; spontaneous abortion |
| Scheller 2017‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 27 years | Vaccinated: 1774 Unvaccinated: 7096 |
Prevalence odds ratio (short‐term) | 1.15 (0.93 to 1.42) | Matched on age, calendar year of pregnancy onset and propensity score (age at pregnancy onset, place of birth, married or living with partner, level of education, household income, pregnancy history, smoking, body mass index, medical history, health care utilisation | Cohort; preterm birth |
| Scheller 2017‐DNK | Gardasil (Merck quadrivalent) | Female, 12 to 27 years | Vaccinated: 501 Unvaccinated: 2004 |
Hazard ratio (short‐term) | 2.43 (0.45 to 13.21) | Matched on age, calendar year of pregnancy onset and propensity score (age at pregnancy onset, place of birth, married or living with partner, level of education, household income, pregnancy history, smoking, body mass index, medical history, health care utilisation | Cohort; stillbirth |
| Kalliala 2021‐FIN | Cervarix (GSK bivalent) | Female, 15 to 22 years | Vaccinated: 6226 Unvaccinated: 19,849 |
Odds ratio (short‐term) | 0.51 (0.30 to 0.87) | Unadjusted | RCT extension; preterm birth |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 1365 Unvaccinated: 1783 |
Relative risk | 1.15 (0.86 to 1.54) | Age at vaccination | RCT extension; miscarriage |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 1365 | Relative risk | 1.06 (0.79 to 1.42) | Calendar year | RCT extension; miscarriage |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Unvaccinated: 1783 | Relative risk | 1.03 (0.78 to 1.35) | Age at conception | RCT extension; miscarriage |
| Krasnopolsky 2020‐RUS | NR | Female, 18 to 36 years | Vaccinated: 320 Unvaccinated: 120 |
Odds ratio (short‐term) | 0.57 (0.32 to 1.03) | Unadjusted | Cross‐sectional; preterm birth |
| Krasnopolsky 2020‐RUS | NR | Female, 18 to 36 years | Vaccinated: 320 Unvaccinated: 120 |
Odds ratio (short‐term) | 0.34 (0.15 to 0.80) | Unadjusted | Cross‐sectional; miscarriage |
| Krasnopolsky 2020‐RUS | NR | Female, 18 to 36 years | Vaccinated: 320 Unvaccinated: 120 |
Odds ratio (short‐term) | 0.05 (0.00 to 1.05) | Unadjusted | Cross‐sectional; congenital malformations |
| Xu 2021‐GBR | Cervarix (GSK bivalent) | Female, 12 to 13 years | Pre‐vaccine: 5134 Post‐vaccine: 131 |
Odds ratio (short‐term; 2006‐16 vs 2015‐16) | 0.71 (0.28 to 1.77) | Smoking during pregnancy, deprivation, marital status, BMI, parity, maternal age and year of infant delivery | Pre‐ vs post‐vaccine introduction; preterm birth |
BMI: body mass index; H1N1: influenza A subtype H1N1; NR: not reported; RCT: randomised controlled trial
55. Risk of bias summary: pregnancy and neonatal outcomes.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Baril 2015‐GBR | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Bukowinski 2020‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Faber 2019‐DNK | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Scheller 2017‐DNK | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Kalliala 2021‐FIN | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Kreimer 2011‐CRI | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Krasnopolsky 2020‐RUS | Critical | Critical | Low | Moderate | Low | Low | Low | Critical |
| Xu 2021‐GBR | Serious | Low | Low | Low | Low | Low | Low | Serious |
Six studies were included that reported on adverse pregnancy and neonatal outcomes following HPV vaccination (Baril 2015‐GBR; Bukowinski 2020‐USA; Faber 2019‐DNK; Krasnopolsky 2020‐RUS; Scheller 2017‐DNK; Xu 2021‐GBR).
Foetal abnormality
One study reported on major birth defects following HPV vaccination in 15‐ to 25‐year‐old women in the UK (Baril 2015‐GBR). There was no association between HPV vaccination and major birth defects (OR 0.89, 95% CI 0.29 to 2.71).
One study reported on structural birth defects in infants of women aged 17 to 28 years in the USA (Bukowinski 2020‐USA). A negative association was found between exposure to HPV vaccine during pregnancy and structural birth defects (1 study, 2281 events; HR 0.67, 95% CI 0.47 to 0.96).
One study reported on congenital malformations in infants of vaccinated HPV negative women and unvaccinated HPV positive women in Russia (Krasnopolsky 2020‐RUS). There were 3/120 (2.5%) congenital malformations in the unvaccinated group and 0/320 (0%) in the vaccinated group. There was no association between HPV vaccination during pregnancy and congenital malformations (OR 0.05, 95% CI 0.00 to 1.05).
One study reported on major birth defects in infants born to women who received HPV vaccination during pregnancy in Denmark (Scheller 2017‐DNK). There was no association between HPV vaccination and major birth defects (prevalence odds ratio 1.19, 95% CI 0.90 to 1.58).
Cervical cerclage and incompetence
No studies were identified that reported on this outcome.
Miscarriage
One study reported on spontaneous abortion following HPV vaccination in 15‐ to 25‐year‐old women in the UK (Baril 2015‐GBR). There was no evidence of increased risk of spontaneous abortion during the first 23 weeks of gestation (HR 1.34, 95% CI 0.81 to 2.24) when receiving HPV vaccination in a risk window 30 days prior to and 45 days following gestation.
One study reported on spontaneous abortion in women aged 17 to 28 years in the USA (Bukowinski 2020‐USA). No association was found between exposure to HPV vaccine during pregnancy and spontaneous abortion (1 study, 13,775 spontaneous abortion events; HR 1.05, 95% CI 0.94 to 1.18).
One study reported on spontaneous abortion following HPV vaccination during pregnancy in Denmark (Faber 2019‐DNK). There was no association between HPV vaccination during pregnancy and spontaneous abortion within the first seven weeks gestation (rate ratio 1.08, 95% CI 0.87 to 1.34).
One study reported on spontaneous miscarriage in vaccinated HPV‐negative women and unvaccinated HPV‐positive women in Russia (Krasnopolsky 2020‐RUS). There were 14/120 (11.7%) spontaneous miscarriages in the unvaccinated group and 15/320 (4.7%) in the vaccinated group. There was no association between HPV vaccination during pregnancy and miscarriage (OR 0.34, 95% CI 0.15 to 0.80).
One study reported on spontaneous abortion in infants born to women who received HPV vaccination during pregnancy in Denmark (Scheller 2017‐DNK). There was no association between HPV vaccination and spontaneous abortion (HR 0.71, 95% CI 0.45 to 1.14).
Pre‐term birth
One study reported on premature birth following HPV vaccination in 15‐ to 25‐year‐old women in the UK (Baril 2015‐GBR). There was no association between HPV vaccination and pre‐term delivery (OR 0.67, 95% CI 0.28 to 1.67).
One study reported on spontaneous preterm labour/delivery in women aged 17 to 28 years in the USA (Bukowinski 2020‐USA). No association was found between exposure to HPV vaccine during pregnancy and spontaneous preterm labour/delivery (1 study, 5603 preterm births; HR 0.92, 95% CI 0.76 to 1.13).
One study reported on preterm births in vaccinated HPV‐negative women and unvaccinated HPV‐positive women in Russia (Krasnopolsky 2020‐RUS). There were 10/120 (8.3%) preterm births in the unvaccinated group and 25/320 (7.8%) in the vaccinated group. There was no association between HPV vaccination and preterm birth (OR 0.57, 95% CI 0.32 to 1.03).
One study reported on preterm birth in infants born to women who received HPV vaccination during pregnancy in Denmark (Scheller 2017‐DNK). There was no association between HPV vaccination and preterm birth (prevalence OR 1.15, 95% CI 0.93 to 1.42).
One study reported on preterm birth in babies born in the UK (Xu 2021‐GBR). There was no association between preterm birth and routine HPV vaccination (OR 0.71, 95% CI 0.28 to 1.77).
Perinatal mortality
One study reported on infant mortality following HPV vaccination during pregnancy in Denmark (Faber 2019‐DNK). There was no association between HPV vaccination during pregnancy and infant mortality (HR 0.94, 95% CI 0.53 to 1.67).
Neonatal intensive care unit (NICU) admission
No studies reported on this outcome.
Stillbirth
One study reported on stillbirth following HPV vaccination in 15‐ to 25‐year‐old women in the UK (Baril 2015‐GBR). There were seven stillbirths, three in the exposed and four in the non‐exposed cohort. There was no association between HPV vaccination during pregnancy and stillbirth (OR 2.29, 95% CI 0.51 to 10.32).
One study reported on stillbirth following HPV vaccination during pregnancy in Denmark (Faber 2019‐DNK). There was no association between HPV vaccination during pregnancy and stillbirth (OR 0.96, 95% CI 0.57 to 1.61).
One study reported on stillbirth in infants born to women who received HPV vaccination during pregnancy in Denmark (Scheller 2017‐DNK). There was no association between HPV vaccination and stillbirth (HR 2.43, 95% CI 0.45 to 13.21).
All‐cause mortality
See Table 58 for effect estimates and Table 59 for the risk of bias summary of included studies on all‐cause mortality. Neither study reported on causes of death.
56. Secondary clinical outcomes effect estimates: all‐cause mortality.
| Study | Vaccine | Population (sex, age) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Thomsen 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 11 to 17 years | Vaccinated: 313,894 person‐years Unvaccinated: 313,885 person‐years |
Incidence rate ratio (short‐term) | 0.52 (0.27 to 0.97) | Age, calendar year of cohort entry, histories of hospital‐diagnosed asthma, diabetes, infections and mental disorders, number of general practitioner contacts within the past 5 years, previous psychometric tests or talk therapy with a general practitioner, a previous psychologist or psychiatrist visit in primary care, parental education, parental employment status, parental annual income, parental marital status and parental ethnicity | Cohort |
| Jemal 2013‐USA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, NR | NR | Average annual percent change (short‐term; 2000 vs 2009) | ‐1.9 (2000‐2009) and ‐0.9 (2005‐2009) | Unadjusted | Pre‐ vs post‐vaccine introduction |
Vaccinated: vaccinated; Unvaccinated: control
NR: not reported
57. Risk of bias summary: all‐cause mortality.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Thomsen 2020‐DNK | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Jemal 2013‐USA | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
Two studies were included that evaluated all‐cause mortality following HPV vaccination (Jemal 2013‐USA; Thomsen 2020‐DNK). One study was a cohort study (Thomsen 2020‐DNK) and the other (Jemal 2013‐USA) was a pre‐ versus post‐vaccine introduction study.
In the short term, there was a negative association between HPV vaccination and death (IRR 0.52, 95% CI 0.27 to 0.97) in the cohort study (Thomsen 2020‐DNK). The other study reported a decrease in the rate of all‐cause mortality from 2000 to 2009 (Jemal 2013‐USA).
Serious adverse events
No studies were identified that reported on population‐level rates of serious adverse events following HPV vaccination.
Incident HPV infection
See Table 60, Table 61 and Table 62 for effect estimates and Table 63 for the risk of bias summary of included studies on incident HPV infection.
58. Secondary clinical outcomes effect estimates: incident HPV 16/18 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Donken 2018‐NLD | Cervarix (GSK bivalent) | Female, 14 to 16 years | Vaccinated: 905 Unvaccinated: 763 |
Vaccine effectiveness (HPV 16/18; long‐term) | 78.9% (69.2% to 85.6%) | Age, urbanisation degree, history of smoking, contraception use and sex | Cohort |
| Hoes 2021‐NLD | Cervarix (GSK bivalent) | Female, 12 to 13 years | Vaccinated: 1098 Unvaccinated: 929 |
Vaccine effectiveness (HPV 16/18; medium‐term) | 84.0% (27.0% to 96.5%) | Age, ethnicity, ever had sexual intercourse and ever used contraception | Cohort |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2019 Unvaccinated: 1479 |
Vaccine effectiveness (HPV 16/18; 3 doses; long‐term) | 66.4% (53.6% to 76.3%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections | RCT extension |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2166 Unvaccinated: 1479 |
Vaccine effectiveness (HPV 16/18; 2 doses; long‐term) | 67.7% (55.2% to 77.2%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections | RCT extension |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2858 Unvaccinated: 1479 |
Vaccine effectiveness (HPV 16/18; 1 dose; long‐term) | 63.5% (51.2% to 73.1%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections | RCT extension |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 1365 Unvaccinated: 1783 | Vaccine efficacy (HPV 16/18; 1 dose; long‐term) | 53.9% (‐57.1% to 92.4%) | Age‐ and location‐matched | RCT extension |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 1365 Unvaccinated: 1783 | Vaccine efficacy (HPV 16/18; 2 doses; long‐term) | 58.4% (‐110.9% to 97.9%) | Age‐ and location‐matched | RCT extension |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 1365 Unvaccinated: 1783 | Vaccine efficacy (HPV 16/18; 3 doses; long‐term) | 84.9% (69.8% to 93.2%) | Age‐ and location‐matched | RCT extension |
HPV: human papillomavirus; RCT: randomised controlled trial
59. Secondary clinical outcomes effect estimates: incident HPV 6/11/16/18 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent) | Male, 16 to 30 years | Vaccinated: 109 Unvaccinated: 139 |
Prevalence ratio (HPV 6/11/16/18; medium‐term) | 0.56 (0.24 to 1.31) | Age group, city, highest level of education, race/ethnicity, sexual orientation, laboratory‐confirmed HIV status, self‐reported lifetime history of STBBIs, lifetime smoking history, risk of alcohol‐related harm in the past 6 months, lifetime illicit drug use, lifetime poppers use, number of male anal sex partners in the past 6 months, sexual activity | Cohort |
| Ma 2017‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 24 years* | Vaccinated: 58 Unvaccinated: 104 |
Odds ratio (HPV 6/11/16/18; short‐term) | 0.36 (0.09 to 1.43) | Lifetime number of male sex partners, sexual behaviour in the past 6 months | Cohort; *age at outcome |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2019 Unvaccinated: 1479 |
Vaccine effectiveness (HPV 6/11/16/18; 3 doses; long‐term) | 54.7% (40.9% to 65.0%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections | RCT extension |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2166 Unvaccinated: 1479 |
Vaccine effectiveness (HPV 6/11/16/18; 2 doses; long‐term) | 59.0% (46.9% to 69.1%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections | RCT extension |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2858 Unvaccinated: 1479 |
Vaccine effectiveness (HPV 6/11/16/18; 1 dose; long‐term) | 54.1% (41.8% to 64.1%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections | RCT extension |
| Wissing 2019‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 63 Unvaccinated: 434 |
Hazard ratio (HPV 6/11/16/18; at least 1 dose; medium‐term) | 0.19 (0.07 to 0.55) | Age, race, smoking status, age at first coitus, number of lifetime sex partners, same‐sex partners and/or concurrent sex partners, condom use, average frequency of coitus with HITCH partner per week, duration of the sexual relationship | Cohort; *age at outcome |
| Wissing 2019‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 63 Unvaccinated: 434 |
Hazard ratio (HPV 6/11/16/18; 1 dose; medium‐term) | 0.21 (0.06 to 0.76) | Age, race, smoking status, age at first coitus, number of lifetime sex partners, same‐sex partners and/or concurrent sex partners, condom use, average frequency of coitus with HITCH partner per week, duration of the sexual relationship | Cohort; *age at outcome |
| Wissing 2019‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 63 Unvaccinated: 434 |
Hazard ratio (HPV 6/11/16/18; at least 2 doses; medium‐term) | 0.43 (0.23 to 0.81) | Age, race, smoking status, age at first coitus, number of lifetime sex partners, same‐sex partners and/or concurrent sex partners, condom use, average frequency of coitus with HITCH partner per week, duration of the sexual relationship | Cohort; *age at outcome |
HPV: human papillomavirus; RCT: randomised controlled trial; STBBI: sexually transmitted and blood‐borne infections
60. Secondary clinical outcomes effect estimates: incident HPV 6/11/16/18/31/33/45/52/58 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent) | Male 16 to 30 years | Vaccinated: 109 Unvaccinated: 139 |
Prevalence ratio (HPV 6/11/16/18/31/33/45/52/58; medium‐term) | 0.80 (0.43 to 1.49) | Age group, city, highest level of education, race/ethnicity, sexual orientation, laboratory‐confirmed HIV status, self‐reported lifetime history of STBBIs, lifetime smoking history, risk of alcohol‐related harm in the past 6 months, lifetime illicit drug use, lifetime poppers use, number of male anal sex partners in the past 6 months, sexual activity | Cohort |
| Donken 2018‐NLD | Cervarix (GSK bivalent) | Female, 14 to 16 years | Vaccinated: 905 Unvaccinated: 763 |
Vaccine effectiveness (HPV 6/11/16/18/31/33/45/52/58; long‐term) | 32.3% (20.2% to 42.4%) | Age, urbanisation degree, history of smoking, contraception use and sex | Cohort |
HPV: human papillomavirus; STBBI: sexually transmitted and blood‐borne infections
61. Risk of bias summary: incident HPV infection.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Incident HPV 16/18 infection | ||||||||
| Donken 2018‐NLD | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Hoes 2021‐NLD | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Sankaranarayanan 2018‐IND | Moderate | Low | Low | Low | Moderate | Low | Low | Moderate |
| Kreimer 2011‐CRI | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Incident HPV 6/11/16/18 infection | ||||||||
| Chambers 2022‐CAN | Moderate | Low | Moderate | Low | Moderate | Low | Low | Moderate |
| Ma 2017‐USA | Serious | Low | Moderate | Low | Moderate | Low | Low | Serious |
| Sankaranarayanan 2018‐IND | Moderate | Low | Low | Low | Moderate | Low | Low | Moderate |
| Wissing 2019‐CAN | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Incident HPV 6/11/16/18/31/33/45/52/58 infection | ||||||||
| Chambers 2022‐CAN | Moderate | Low | Moderate | Low | Moderate | Low | Low | Moderate |
| Donken 2018‐NLD | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
HPV: human papillomavirus
Seven studies were identified that reported on incident HPV infection following HPV vaccination (Chambers 2022‐CAN; Donken 2018‐NLD; Hoes 2021‐NLD; Kreimer 2011‐CRI; Ma 2017‐USA; Sankaranarayanan 2018‐IND; Wissing 2019‐CAN).
HPV 16/18
Two cohort studies (Donken 2018‐NLD; Hoes 2021‐NLD) and two RCT extension studies (Kreimer 2011‐CRI; Sankaranarayanan 2018‐IND) reported on incident HPV 16/18 infections following HPV vaccination.
Vaccine effectiveness against incident HPV 16/18 infection ranged from 77.5% to 84% in the cohort studies and 66.4% to 84.9% in the RCT extension studies.
Vaccine effectiveness for partial schedules (i.e. one or two doses) ranged in the RCT extension studies from 58.4% to 67.7% for two doses and 53.9% to 63.5% for one dose.
HPV 6/11/16/18
Three cohort studies (Chambers 2022‐CAN; Ma 2017‐USA; Wissing 2019‐CAN) and one RCT extension study (Sankaranarayanan 2018‐IND) reported on incident HPV 6/11/16/18 infections following HPV vaccination.
Two cohort studies reported a reduced odds of incident HPV 6/11/16/18 infection following HPV vaccination but with confidence intervals that included no difference (Chambers 2022‐CAN; Ma 2017‐USA). The other cohort study reported a reduced risk of incident HPV 6/11/16/18 infection following HPV vaccination with at least two doses (HR 0.43, 95% CI 0.23 to 0.81) and at least one dose (HR 0.19, 95% CI 0.07 to 0.55).
Vaccine effectiveness against incident HPV 6/11/16/18 infection ranged between 54.7% following three doses, 59% following two doses and 54.1% following one dose of HPV vaccine in the RCT extension study (Sankaranarayanan 2018‐IND).
HPV 6/11/16/18/31/33/45/52/58
Two cohort studies reported on incident HPV 6/11/16/18/31/33/45/52/58 infection following HPV vaccination (Chambers 2022‐CAN; Donken 2018‐NLD). Vaccine effectiveness was 33% (95% CI 19.1% to 44.6%) in one study (Donken 2018‐NLD) and the prevalence ratio was 0.80 (95% CI 0.43 to 1.49) in the other (Chambers 2022‐CAN).
Persistent HPV infection
See Table 64, Table 65 and Table 66 for effect estimates and Table 67 for the risk of bias summary of included studies on persistent HPV infection.
62. Secondary clinical outcomes effect estimates: persistent HPV 16/18 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Donken 2018‐NLD | Cervarix (GSK bivalent) | Female, 14 to 16 years | Vaccinated: 883 Unvaccinated: 752 |
Vaccine effectiveness (HPV 16/18; long‐term) | 95.8% (86.6% to 98.7%) | Age, urbanisation degree, any history of smoking, any history of contraception use and any history of sex | Cohort |
| Ounchanum 2024‐THA/VNM | Cervarix (GSK bivalent) | Female, 12 to 24 years | Vaccinated: 47 Unvaccinated: 145 |
Prevalence ratio (HPV 16/18); long‐term – not receiving vaccination | 1.37 (1.08 to 1.74) | HIV, education, ever been pregnant, age < 20, BMI ≥ 20 kg/m2, alcohol, tobacco, substance use, lifetime number of sex partners ≥ 6, number of sex partners, past 6 months, condom use with vaginal sex, past 6 months, history of STIs at baseline, laboratory diagnosis of STIs during the study | Cohort |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 1460 Unvaccinated: 1260 |
Vaccine effectiveness (HPV 16/18; 3 doses; long‐term) | 93.3% (77.5% to 99.7%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between dates of marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections per participant | RCT extension |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 1452 Unvaccinated: 1260 |
Vaccine effectiveness (HPV 16/18; 2 doses; long‐term) | 93.1% (77.3% to 99.8%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between dates of marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections per participant | RCT extension |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2135 Unvaccinated: 1260 |
Vaccine effectiveness (HPV 16/18; 1 dose; long‐term) | 95.4% (85.0% to 99.9%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between dates of marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections per participant | RCT extension |
BMI: body mass index; HPV: human papillomavirus; RCT: randomised controlled trial; STI: sexually transmitted infection
63. Secondary clinical outcomes effect estimates: persistent HPV 6/11/16/18 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent) | Male, 16 to 30 years | Vaccinated: 109 Unvaccinated: 139 |
Prevalence ratio (HPV 6/11/16/18; medium‐term) | 0.53 (0.25 to 1.14) | Age group, city, highest level of education, race/ethnicity, sexual orientation, laboratory‐confirmed HIV status, self‐reported lifetime history of STBBIs, lifetime smoking history, risk of alcohol‐related harm in the past 6 months, lifetime illicit drug use, lifetime poppers use, number of male anal sex partners in the past 6 months, sexual activity | Cohort |
| Wissing 2019‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 63 Unvaccinated: 434 |
Odds ratio (HPV 6/11/16/18; at least 1 dose; medium‐term) | 0.13 (0.03 to 0.63) | Age, race, smoking status, age at first coitus, number of lifetime sex partners (coitus), whether the individual had same‐sex partners and/or concurrent sex partners, condom use, average frequency of coitus with HITCH partner per week, and duration of the sexual relationship | Cohort; *age at outcome |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 1460 Unvaccinated: 1260 |
Vaccine effectiveness (HPV 6/11/16/18; 3 doses; long‐term) | 90.3% (71.9% to 98.5%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between dates of marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections per participant | RCT extension |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 1452 Unvaccinated: 1260 |
Vaccine effectiveness (HPV 6/11/16/18; 2 doses; long‐term) | 93.7% (79.8% to 99.8%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between dates of marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections per participant | RCT extension |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 2135 Unvaccinated: 1260 |
Vaccine effectiveness (HPV 6/11/16/18; 1 dose; long‐term) | 93.4% (81.1% to 99.1%) | Study site, birth cohort, religion, total number of pregnancies, age at first cervical cell sample collection, time between dates of marriage and first cervical sample collection, delayed cervical sample collection, number of cervical cell sample collections per participant | RCT extension |
HPV: human papillomavirus; RCT: randomised controlled trial; STBBI: sexually transmitted and blood‐borne infections
64. Secondary clinical outcomes effect estimates: persistent HPV 6/11/16/18/31/33/45/52/58 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent) | Male, 16 to 30 years | Vaccinated: 109 Unvaccinated: 139 |
Prevalence ratio (HPV 6/11/16/18/31/33/45/52/58; medium‐term) | 0.65 (0.33 to 1.27) | Age group, city, highest level of education, race/ethnicity, sexual orientation, laboratory‐confirmed HIV status, self‐reported lifetime history of STBBIs, lifetime smoking history, risk of alcohol‐related harm in the past 6 months, lifetime illicit drug use, lifetime poppers use, number of male anal sex partners in the past 6 months, sexual activity | Cohort |
| Donken 2018‐NLD | Cervarix (GSK bivalent) | Female, 14 to 16 years | Vaccinated: 883 Unvaccinated: 752 |
Vaccine effectiveness (HPV 6/11/16/18/31/33/45/52/58; long‐term) | 51.7% (35.9% to 63.7%) | Age, urbanisation degree, any history of smoking, any history of contraception use, and any history of sex | Cohort |
HPV: human papillomavirus; STBBI: sexually transmitted and blood‐borne infections
65. Risk of bias summary: persistent HPV infection.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Persistent HPV 16/18 infection | ||||||||
| Donken 2018‐NLD | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Ounchanum 2024‐THA/VNM | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Sankaranarayanan 2018‐IND | Moderate | Low | Low | Low | Moderate | Low | Low | Moderate |
| Persistent HPV 6/11/16/18 infection | ||||||||
| Chambers 2022‐CAN | Moderate | Low | Moderate | Low | Moderate | Low | Low | Moderate |
| Sankaranarayanan 2018‐IND | Moderate | Low | Low | Low | Moderate | Low | Low | Moderate |
| Wissing 2019‐CAN | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Persistent HPV 6/11/16/18/31/33/45/52/58 infection | ||||||||
| Chambers 2022‐CAN | Moderate | Low | Moderate | Low | Moderate | Low | Low | Moderate |
| Donken 2018‐NLD | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
HPV: human papillomavirus
Five studies were identified that reported on persistent HPV infection following HPV vaccination (Chambers 2022‐CAN; Donken 2018‐NLD; Ounchanum 2024‐THA/VNM; Sankaranarayanan 2018‐IND; Wissing 2019‐CAN).
HPV 16/18
Two cohort studies (Donken 2018‐NLD; Ounchanum 2024‐THA/VNM) and one RCT extension study (Sankaranarayanan 2018‐IND) reported on persistent HPV 16/18 infection. In one cohort study, vaccine effectiveness was 97.7% (95% CI 83.5% to 99.7%) (Donken 2018‐NLD), and in the other the prevalence ratio was 1.37 (95% CI 1.08 to 1.74) (Ounchanum 2024‐THA/VNM). Vaccine effectiveness was 93.3% (95% CI 77.5% to 99.7%) in the RCT extension study (Sankaranarayanan 2018‐IND).
The effectiveness of two doses (93.1%, 95% CI 77.3% to 99.8%) and one dose (95.4%, 95% CI 85.0% to 99.9%) were also reported by the RCT extension study (Sankaranarayanan 2018‐IND).
HPV 6/11/16/18
Two cohort studies (Chambers 2022‐CAN; Wissing 2019‐CAN) and one RCT extension study (Sankaranarayanan 2018‐IND) reported on persistent HPV 6/11/16/18 infection. One cohort study reported an odds ratio of 0.13 (95% CI 0.03 to 0.63) for persistent infection (Wissing 2019‐CAN) and the other a prevalence ratio of 0.53 (95% CI 0.25 to 1.14) following HPV vaccine (Chambers 2022‐CAN). Vaccine effectiveness was 90.3% (71.9% to 98.5%) in the RCT extension.
The effectiveness of two doses (93.7%, 95% CI 79.8% to 99.8%) and one dose (93.4%, 95% CI 81.1% to 99.1%) were also reported by the RCT extension study (Sankaranarayanan 2018‐IND).
HPV 6/11/16/18/31/33/45/52/58
Two cohort studies reported on persistent HPV 6/11/16/18/31/33/45/52/58 infection (Chambers 2022‐CAN; Donken 2018‐NLD). Vaccine effectiveness was reported at 50.4% (95% CI 29.7% to 65.1%) in one study (Donken 2018‐NLD) and a prevalence ratio of 0.65 (95% CI 0.33 to 1.27) in the other (Chambers 2022‐CAN).
Prevalent HPV infection
See Table 68, Table 69, Table 70 and Table 71 for effect estimates and Table 72 for the risk of bias summary of included studies on incident HPV infection.
66. Secondary clinical outcomes effect estimates: prevalent HPV 16/18 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Batmunkh 2020‐MNG | Gardasil (Merck quadrivalent) | Female, 16 to 26 years* | Vaccinated: 87 Unvaccinated: 266 |
Prevalence ratio (HPV 16/18; 1 dose; long‐term) | 0.08 (0.01 to 0.56) | Employment status and income | Cross‐sectional; *age at outcome |
| Batmunkh 2019‐MNG | Gardasil (Merck quadrivalent) | Female, 16 to 26 years* | Vaccinated: 726 Unvaccinated: 790 |
Risk ratio (HPV 16/18; 3 doses; long‐term) | 0.31 (0.22 to 0.45) | Unadjusted | Cross‐sectional; *age at outcome |
| Bobadilla 2024‐PAR | Gardasil (Merck quadrivalent); | Female, 18 to 25 years | Vaccinated: 104 Unvaccinated: 150 |
Prevalence ratio (HPV 16/18) | 0.35 (0.10 to 1.20) | Unadjusted | Cross‐sectional |
| Bogaards 2019‐NLD | Cervarix (GSK bivalent) | Female, 16 to 24 years* | Vaccinated: 1305 Unvaccinated: 799 |
Odds ratio (HPV 16/18; ≥ 1 dose; long‐term) | 0.09 (0.06 to 0.14) | Age, migration background, education level, number of sex partners last 6 months, lifetime number of sex partners, age at sexual debut, history of STI, hormonal contraceptives use, STI‐related symptoms and age vaccination was offered | Cross‐sectional; *age at outcome |
| Carnalla 2021‐MEX | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 9 to 10 years | Vaccinated: 93 Unvaccinated: 88 |
Prevalence ratio (HPV 16/18; long‐term) | 0.16 (0.02 to 1.28) | Unadjusted | Cross‐sectional |
| Carozzi 2018‐ITA | Gardasil (Merck quadrivalent) | Female, 18 to 30 years* | Vaccinated: 771 Unvaccinated: 537 |
Odds ratio (HPV 16/18; long‐term) | 0.11 (0.04 to 0.30) | Marital status, smoking status, number of sexual partners in the past 6 months, number of lifetime sexual partners and sexually transmitted diseases | Cross‐sectional; *age at outcome |
| Combita 2021‐COL | Gardasil (Merck quadrivalent) | Female, 18 to 25 years* | Vaccinated: 1986 Unvaccinated: 1287 |
Vaccine efficacy (HPV 16/18; long‐term) | 61.5 (54.3 to 67.6) | Age, socioeconomic stratum, residence area, marital status, smoking, age of sexual debut, number of sexual partners, occasional sexual partners, contraceptive method and history of sexually transmitted diseases | Cross‐sectional; *age at outcome |
| Cummings 2012‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 17 years* | Vaccinated: 75 Unvaccinated: 150 |
Odds ratio (HPV 16/18) | 3.6 (1.2 to 10.6) | Matched with two historical controls from a previous cross‐sectional study by age at enrolment, clinic site and reported sexual activity at the time of enrolment | Cross‐sectional; *age at outcome |
| Delere 2014‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 20 to 25 years* | Vaccinated: 223 Unvaccinated: 512 |
Prevalence ratio (HPV 16/18) | 0.62 (0.43 to 0.89) | Unadjusted | Cross‐sectional; *age at outcome |
| Enerly 2019‐NOR | Gardasil (Merck quadrivalent) | Female, 18 to 20 years* | Vaccinated: 239 Unvaccinated: 73 |
Prevalence ratio (HPV 16/18; ≥ 1 dose; long‐term) | 0.11 (0.01 to 1.30) | Lifetime number of sexual partners, age at sexual debut and time since last sexual intercourse | Cross‐sectional; *age at outcome |
| Feder 2019‐USA | Gardasil (Merck quadrivalent) | Female, 21 to 29 years* | Vaccinated: 221 Unvaccinated: 143 |
Risk ratio (HPV 16/18; ≥ 1 dose; long‐term) | 0.50 (0.19 to 1.32) | Unadjusted | Cross‐sectional; *age at outcome |
| Gonzalez 2020‐ARG | Gardasil (Merck quadrivalent) | Female, 15 to 17 years* | Vaccinated: 1224 Unvaccinated: 957 |
Odds ratio (HPV 16/18; medium‐term) | 0.07 (0.04 to 0.12) | Unadjusted | Cross‐sectional; *age at outcome |
| Heard 2017‐FRA | Gardasil (Merck quadrivalent) | Female, 18 to 25 years* | Vaccinated: 822 Unvaccinated: 1893 |
Prevalence ratio (HPV 16/18; ≥ 1 dose) | 0.01 (0.00 to 0.07) | Unadjusted | Cross‐sectional; *age at outcome |
| Hiramatsu 2021‐JPN | Gardasil (Merck quadrivalent) | Female, 20 to 21 years* | Vaccinated: 877 Unvaccinated: 170 |
Odds ratio (HPV 16/18) | 0.06 (0.00 to 0.92) | Unadjusted | Cross‐sectional; *age at outcome |
| Hirth 2017‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 30 years* | Vaccinated: 668 Unvaccinated: 2372 |
Prevalence ratio (oral HPV 16/18) | 0.31 (0.07 to 1.31) | Unadjusted | Cross‐sectional; *age at outcome |
| Jeannot 2018‐CHE | Gardasil (Merck quadrivalent) | Female, 18 to 23 years* | Vaccinated: 284 Unvaccinated: 125 |
Prevalence ratio (HPV 16/18) | 0.15 (0.04 to 0.53) | Unadjusted | Cross‐sectional; *age at outcome |
| Kahn 2016‐USA | Gardasil (Merck quadrivalent) | Female, 13 to 26 years* | Vaccinated: 286 Unvaccinated: 485 |
Odds ratio (HPV 16/18; 2006‐7 vs 2013‐4) | 0.19 (0.12 to 0.31) | Propensity score analysis adjusted for sociodemographic characteristics, gynaecologic history, sexual history and enrolment site. | Repeated cross‐sectional; *age at outcome |
| Kitamura 2023‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 16 to 75 years | Vaccinated: 454 Unvaccinated: 1579 |
Odds ratio (HPV 16/18) | 0.05 (0.01 to 0.20) | Age, educational status, smoking status, number of lifetime sexual partners, age at coitarche, marital status, divorce, number of children, commercial sex work experience, current STI, history of STI | Cross‐sectional |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 112 Unvaccinated: 1783 |
Vaccine efficacy (HPV 16/18; 1 dose) | 82.1 (40.2 to 97.0) | Age‐ and location‐matched | RCT extension |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 62 Unvaccinated: 1783 |
Vaccine efficacy (HPV 16/18; 2 doses) | 83.8 (19.5 to 99.2) | Age‐ and location‐matched | RCT extension |
| Kreimer 2011‐CRI | Cervarix (GSK bivalent) | Female, 18 to 25 years | Vaccinated: 1365 Unvaccinated: 1783 |
Vaccine efficacy (HPV 16/18; 3 doses) | 80.2 (70.7 to 87.0) | Age‐ and location‐matched | RCT extension |
| Kudo 2019‐JPN | Gardasil (Merck quadrivalent) | Female, 20 to 22 years* | Vaccinated: 3167 Unvaccinated: 1386 |
Odds ratio (HPV 16/18) | 0.11 (0.05 to 0.27) | Year of birth and lifetime number of sex partners | Cross‐sectional; *age at outcome |
| Kudo 2019‐JPN | Gardasil (Merck quadrivalent) | Female, 25 to 26 years* | Vaccinated: 150 Unvaccinated: 279 |
Odds ratio (HPV 16/18; long‐term) | 0.06 (0.00 to 1.05) | Unadjusted | Cross‐sectional; *age at outcome |
| Kumakech 2016‐UGA | Cervarix (GSK bivalent) | Female, 15 to 24 years* | Vaccinated: 252 Unvaccinated: 236 |
Odds ratio (HPV 16/18) | 0.08 (0.01 to 0.64) | Age, age at sexual debut and educational level | Cross‐sectional; *age at outcome |
| Laake 2020‐NOR | Gardasil (Merck quadrivalent) | Female, 17 years* | Vaccinated: 6360 Unvaccinated: 5468 |
Relative risk (HPV 16/18) | 0.22 (0.17 to 0.29) | Unadjusted | Cross‐sectional; *age at outcome |
| Latsuzbaia 2019‐LUX | Gardasil (Merck quadrivalent) | Female, 18 to 29 years* | Vaccinated: 216 Unvaccinated: 232 |
Odds ratio (HPV 16/18) | 0.10 (0.01 to 0.82) | Number of lifetime sexual partners, last partnership duration and age | Cross‐sectional; *age at outcome |
| Latsuzbaia 2019‐LUX | Cervarix (GSK bivalent) | Female, 18 to 29 years* | Vaccinated: 216 Unvaccinated: 131 |
Odds ratio (HPV 16/18) | 0.19 (0.02 to 1.62) | Number of lifetime sexual partners, last partnership duration and age | Cross‐sectional; *age at outcome |
| Lee 2022‐THA | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 20 to 45 years | Vaccinated: 493 Unvaccinated: 500 |
Vaccine effectiveness (HPV 16/18) | 84.6% (43.5 to 95.8) | Baseline Pap test results and baseline hrHPV test | Cross‐sectional |
| Lehtinen 2017a‐FIN | Cervarix (GSK bivalent) | Male, 12 to 15 years | Vaccinated: 395 Unvaccinated: 149 |
Relative risk (HPV 16/18) | 0.05 (0.00 to 1.04) | Unadjusted | Cross‐sectional |
| Loenenbach 2023‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female 20 to 25 years | Vaccinated: 348 Unvaccinated: 377 |
Prevalence ratio (HPV 16/18) | 0.5 (0.3 to 1.0) | Age, nationality, education, smoking, number of sexual partners, immunodeficiency and cancer screening | Cross‐sectional |
| Lynge 2020‐DNK | Gardasil (Merck quadrivalent) | Female, 14 years | Vaccinated: 5685 Unvaccinated: 518 |
Relative risk (HPV 16/18) | 0.05 (0.03 to 0.09) | Unadjusted | Cross‐sectional |
| Markowitz 2019‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years | Vaccinated: 2059 Unvaccinated: 2057 |
Prevalence ratio (HPV 16/18; 2007 vs 2015‐2016) | 0.24 (0.18 to 0.32) | Unadjusted | Repeated cross‐sectional |
| Markowitz 2019‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years | Vaccinated: 2420 Unvaccinated: 2081 |
Prevalence ratio (HPV 16/18; 2007 vs 2015‐2016) | 0.64 (0.50 to 0.81) | Unadjusted | Repeated cross‐sectional |
| Mehanna 2019‐GBR | Cervarix (GSK bivalent) | Female, 12 to 13 years | Vaccinated: 123 Unvaccinated: 16 |
Prevalence ratio (oral HPV 16/18) | 0.26 (0.03 to 2.71) | Unadjusted | Cross‐sectional |
| Mehanna 2019‐GBR | Cervarix (GSK bivalent) | Female, 14 to 17 years | Vaccinated: 59 Unvaccinated: 25 |
Prevalence ratio (oral HPV 16/18) | 0.14 (0.01 to 3.43) | Unadjusted | Cross‐sectional |
| Mesher 2018‐GBR | Cervarix (GSK bivalent) | Female, 12 to 15 years | Vaccinated: 1176 Unvaccinated: 117 |
Vaccine effectiveness (HPV 16/18) | 82.0% (60.6 to 91.8) | Age, testing venue type and chlamydia positivity | Repeated cross‐sectional |
| Mesher 2018‐GBR | Cervarix (GSK bivalent) | Female, 16 to 18 years | Vaccinated: 614 Unvaccinated: 289 |
Vaccine effectiveness (HPV 16/18) | 48.7% (20.8 to 66.8) | Age, testing venue type and chlamydia positivity | Repeated cross‐sectional |
| Napolitano 2024‐ITA | Not reported | Female and male, 18 to 30 years | Vaccinated: 490 Unvaccinated: 512 |
Prevalence ratio (HPV 16/18) | 1.04 (0.07 to 16.66) | Unadjusted | Cross‐sectional |
| Nilyanimit 2024‐THA | Cervarix (GSK bivalent) | Female, 16 to 18 years | Vaccinated: 211 Unvaccinated: 376 |
Prevalence ratio (HPV 16/18) | 0.07 (0.00 to 1.14) | No cases in exposed group; age, sexual experience, sexual debut age in years, condom usage | Cross‐sectional |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 20 to 21 years* | Vaccinated: 3962 Unvaccinated: 4008 |
Odds ratio (HPV 16/18; 3 doses) | 0.40 (0.33 to 0.48) | Birth year, SIMD score and age at vaccination | Cross‐sectional; *age at outcome |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 20 to 21 years* | Vaccinated: 391 Unvaccinated: 4008 |
Odds ratio (HPV 16/18; 2 doses) | 0.75 (0.57 to 0.99) | Birth year, SIMD score and age at vaccination | Cross‐sectional; *age at outcome |
| Palmer 2019‐GBR | Cervarix (GSK bivalent) | Female, 20 to 21 years* | Vaccinated: 223 Unvaccinated: 4008 |
Odds ratio (HPV 16/18; 1 dose) | 0.89 (0.63 to 1.25) | Birth year, SIMD score and age at vaccination | Cross‐sectional; *age at outcome |
| Purrinos‐Hermida 2018‐ESP | Cervarix (GSK bivalent) | Female, 18 to 26 years* | Vaccinated: 353 Unvaccinated: 392 |
Prevalence ratio (HPV 16/18) | 0.06 (0.01 to 0.28) | Age group, first intercourse > 16 years old, 3 or more partners along life and 2 or more partners in the last year | Cross‐sectional; *age at outcome |
| Reyburn 2023‐FJI | Gardasil (Merck quadrivalent) | Female, 15 to 23 years | Vaccinated: 189 Unvaccinated: 376 |
Prevalence ratio (3 doses; HPV 16/18) | 0.11 (0.04 to 0.36) | Age, ethnicity and smoking | Cross‐sectional |
| Reyburn 2023‐FJI | Gardasil (Merck quadrivalent) | Female, 15 to 23 years | Vaccinated: 158 Unvaccinated: 376 |
Prevalence ratio (1 dose; HPV 16/18) | 0.19 (0.07 to 0.52) | Age, ethnicity and smoking | Cross‐sectional |
| Saeki 2024‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 16 to 39 years | Vaccinated: 299 Unvaccinated: 1230 |
Odds ratio (HPV 16/18) | 0.03 (0.00 to 0.19) | Unadjusted | Cross‐sectional |
| Saldanha 2020‐PRT | Gardasil (Merck quadrivalent) | Female, < 25 years* | Vaccinated: 951 Unvaccinated: 902 |
Prevalence ratio (HPV 16/18) | 0.27 (0.13 to 0.56) | Unadjusted | Cross‐sectional; *age at outcome |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 818 Unvaccinated: 179 |
Odds ratio (oral HPV 16/18) | 0.4 (0.2 to 1.0) | Age at oral sample collection | Cross‐sectional |
| Sarr 2019‐CAN | Gardasil (Merck quadrivalent) | Female, > 18 years* | Vaccinated: 79 Unvaccinated: 956 |
Vaccine effectiveness (HPV 16/18) | 86.1 (15.0 to 99.7) | Age and number of new sexual partners in the last 12 months | Cross‐sectional; *age at outcome |
| Tanton 2017‐GBR | Cervarix (GSK bivalent) | Female, 18 to 20 years* | Vaccinated: 84 Unvaccinated: 265 |
Odds ratio (HPV 16/18) | 0.46 (0.20 to 1.05) | Age, number of lifetime partners | Repeated cross‐sectional; *age at outcome |
| Tanton 2017‐GBR | Cervarix (GSK bivalent) | Female, 18 to 20 years* | Vaccinated: 84 Unvaccinated: 265 |
Prevalence ratio (HPV 16/18; 1999‐2001 vs 2010‐2012) | 0.48 (0.24 to 0.93) | Age | Repeated cross‐sectional; *age at outcome |
| Van Eer 2021‐NLD | Cervarix (GSK bivalent) | Female, 16 to 24 years* | Vaccinated: 352 Unvaccinated: 190 |
Prevalence ratio (HPV 16/18) | 0.40 (0.23 to 0.70) | Unadjusted | Cross‐sectional; *age at outcome |
| Van Eer 2021‐NLD | Cervarix (GSK bivalent) | Female, 16 to 24 years* | Vaccinated: 352 Unvaccinated: 190 |
Prevalence ratio (concurrent genital‐anal HPV 16/18) | 0.05 (0.01 to 0.34) | Unadjusted | Cross‐sectional; *age at outcome |
| Wendland 2021‐BRA | Gardasil (Merck quadrivalent) | Female, 16 to 25 years* | Vaccinated: 677 Unvaccinated: 5268 |
Risk ratio (HPV 16/18) | 0.40 (0.28 to 0.56) | Unadjusted | Cross‐sectional; *age at outcome |
| Woestenberg 2020‐NLD | Cervarix (GSK bivalent) | Female, 16 to 24 years* | Vaccinated: 357 Unvaccinated: 191 |
Vaccine effectiveness (anal HPV 16/18) | 89.9 (63.0 to 97.2) | Age, education level, history of anal sex, number of sex partners in the past 6 months, sexually transmitted infection‐related symptoms, and use of hormonal contraceptives | Cross‐sectional; *age at outcome |
| Wright 2019‐USA | Gardasil (Merck quadrivalent) | Female, 21 to 34 years* | Vaccinated: 2977 Unvaccinated: 11,176 |
Odds ratio (HPV 16/18) | 0.3 (0.2 to 0.4) | Age | Cross‐sectional; *age at outcome |
| Huyghe 2023‐BEL | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female 20 to 23 years | N = 3008 | Relative risk (HPV 16/18; 2010 vs 2019) | 0.19 (0.14 to 0.27) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Khoo 2022‐MYS | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 18 to 24 years | Vaccinated: 75 Unvaccinated: 1135 |
Prevalence change (HPV 16/18) | ‐91% (‐99% to ‐14.5%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Khoo 2022‐MYS | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 35 to 45 years | Vaccinated: 75 Unvaccinated: 1135 |
Prevalence change (HPV 16/18) | ‐38.2% (‐77.8% to 72.3%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Rebolj 2022‐GBR | Cervarix (GSK bivalent) | Female 24 to 25 years | N = 64274 | Vaccine effectiveness (HPV 16/18) | 90 (89 to 92) | Deprivation and laboratory | Pre‐ vs post‐vaccine introduction |
| Saeki 2024‐JPN | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female, 16 to 39 years | Vaccinated: 382 Unvaccinated: 3984 |
Odds ratio (HPV 16/18; 2011 vs 2021) | 0.56 (0.41 to 0.76) | Unadjusted | Pre‐ vs post‐vaccine introduction |
HPV: human papillomavirus; hrHPV: high‐risk human papillomavirus; RCT: randomised controlled trial; SIMD: Scottish Index of Multiple Deprivation; STI: sexually transmitted infection
67. Secondary clinical outcomes effect estimates: prevalent HPV 6/11/16/18 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Ahrlund‐Richter 2019‐SWE | Gardasil (Merck quadrivalent) | Female, 15 to 23 years* | Vaccinated: 138 Unvaccinated: 30 |
Risk ratio (HPV 6/11/16/18) | 0.26 (0.10 to 0.65) | Unadjusted | Cross‐sectional; *age at outcome |
| Abel 2021‐USA | Gardasil (Merck quadrivalent) | Female and male, 18 to 36 years* | Vaccinated: 198 Unvaccinated: 4801 |
Prevalence ratio (HPV 6/11/16/18; 1 dose) | 0.41 (0.06 to 2.95) | Unadjusted | Cross‐sectional; *age at outcome |
| Abel 2021‐USA | Gardasil (Merck quadrivalent) | Female and male, 18 to 36 years* | Vaccinated: 799 Unvaccinated: 4801 |
Prevalence ratio (HPV 6/11/16/18; 2 or 3 doses) | 0.20 (0.05 to 0.83) | Unadjusted | Cross‐sectional; *age at outcome |
| Balgovind 2024‐AUS | Gardasil (Merck quadrivalent) | Male MSM, 18 to 34 years | Vaccinated: 152 Unvaccinated: 479 |
Prevalence ratio (HPV 6/11/16/18) | 0.8 (0.6 to 1.06) | Unadjusted | Cross‐sectional |
| Balgovind 2024‐AUS | Gardasil (Merck quadrivalent) | Male, 18 to 34 years | Vaccinated: 103 Unvaccinated: 891 |
Prevalence ratio (HPV 6/11/16/18) | 1.01 (0.56 to 1.83) | Unadjusted | Cross‐sectional |
| Baussano 2021‐RWA/BTN | Gardasil (Merck quadrivalent) | Female, 17 to 22 years* | Vaccinated: 962 Unvaccinated: 519 |
Prevalence ratio (HPV 6/11/16/18; Rwanda) | 0.05 (0.01 to 0.17) | Age group, place of birth and reported history of sexual intercourse | Cross‐sectional; *age at outcome |
| Baussano 2021‐RWA/BTN | Gardasil (Merck quadrivalent) | Female, 17 to 22 years* | Vaccinated: 864 Unvaccinated: 77 |
Prevalence ratio (HPV 6/11/16/18; Bhutan) | 0.05 (0.01 to 0.51) | Reported history of sexual intercourse | Cross‐sectional; *age at outcome |
| Baussano 2020‐BTN | Gardasil (Merck quadrivalent) | Female, 17 to 29 years* | Vaccinated: 1053 Unvaccinated: 1338 |
Prevalence ratio (HPV 6/11/16/18) | 0.12 (0.08 to 0.20) | Age group, type of invitation to participate in the survey, age at first sexual intercourse, lifetime number of sexual partners and partner's “extramarital” sexual behaviour | Cross‐sectional; *age at outcome |
| Berenson 2021‐USA | Gardasil (Merck quadrivalent) | Female and male, 18 to 59 years* | Vaccinated: 939 Unvaccinated: 8498 |
Risk ratio (oral HPV 6/11/16/18) | 0.44 (0.19 to 0.99) | Unadjusted | Cross‐sectional; *age at outcome |
| Berenson 2021‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 59 years* | Vaccinated: 723 Unvaccinated: 4164 |
Risk ratio (oral HPV 6/11/16/18) | 0.25 (0.03 to 1.86) | Unadjusted | Cross‐sectional; *age at outcome |
| Berenson 2021‐USA | Gardasil (Merck quadrivalent) | Male, 18 to 59 years* | Vaccinated: 216 Unvaccinated: 4334 |
Risk ratio (oral HPV 6/11/16/18) | 0.10 (0.04 to 0.25) | Unadjusted | Cross‐sectional; *age at outcome |
| Bobadilla 2024‐PAR | Gardasil (Merck quadrivalent) | Female, 18 to 25 years | Vaccinated: 104 Unvaccinated: 150 |
Prevalence ratio (HPV 16/18) | 0.27 (0.10 to 0.75) | Unadjusted | Cross‐sectional |
| Carozzi 2018‐ITA | Gardasil (Merck quadrivalent) | Female, 18 to 30 years* | Vaccinated: 771 Unvaccinated: 537 |
Odds ratio (HPV 6/11/16/18) | 0.10 (0.04 to 0.27) | Marital status, smoking status, number of sexual partners in the past 6 months, number of lifetime sexual partners and sexually transmitted diseases |
Cross‐sectional; *age at outcome |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male, ≤ 23 years | Vaccinated: 118 Unvaccinated: 349 |
Prevalence ratio (anal HPV 6/11/16/18) | 0.64 (0.42 to 0.99) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male, > 23 years | Vaccinated: 112 Unvaccinated: 349 |
Prevalence ratio (anal HPV 6/11/16/18) | 0.82 (0.55 to 1.20) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male, 16 to 30 years* | Vaccinated: 136 Unvaccinated: 349 |
Prevalence ratio (anal HPV 6/11/16/18; 3 doses) | 0.75 (0.52 to 1.10) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional; *age at outcome |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male, 16 to 30 years* | Vaccinated: 184 Unvaccinated: 349 |
Prevalence ratio (HPV 6/11/16/18; at least 2 doses) | 0.77 (0.55 to 1.07) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional; *age at outcome |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male 16 to 30 years* | Vaccinated: 241 Unvaccinated: 349 |
Prevalence ratio (HPV 6/11/16/18; at least 1 dose) | 0.73 (0.54 to 1.00) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional; *age at outcome |
| Chow 2017‐AUS | Gardasil (Merck quadrivalent) | Male, ≤ 25 years* | Vaccinated: 1217 Unvaccinated: 250 |
Prevalence ratio (HPV 6/11/16/18; 2004‐7 vs 2007‐15) | 0.50 (0.37 to 0.70) | Unadjusted | Repeated cross‐sectional; *age at outcome |
| Chow 2019‐AUS | Gardasil (Merck quadrivalent) | Male, 17 to 19 years* | Vaccinated: 146 Unvaccinated: 152 |
Prevalence ratio (Penile HPV 6/11/16/18; 2014‐5 vs 2016‐7) | 0.28 (0.03 to 2.62) | Age and source of recruitment | Repeated cross‐sectional; *age at outcome |
| Chow 2021a‐AUS | Gardasil (Merck quadrivalent) | Male, 16 to 20 years* | Vaccinated: 193 Unvaccinated: 193 |
Prevalence ratio (Anal HPV 6/11/16/18) | 0.24 (0.14 to 0.42) | Age, circumcision and sex with women | Repeated cross‐sectional; *age at outcome |
| Chow 2021a‐AUS | Gardasil (Merck quadrivalent) | Male, 16 to 20 years* | Vaccinated: 179 Unvaccinated: 177 |
Prevalence ratio (Penile HPV 6/11/16/18) | 0.48 (0.24 to 0.97) | Age, circumcision and sex with women | Repeated cross‐sectional; *age at outcome |
| Chow 2021a‐AUS | Gardasil (Merck quadrivalent) | Male, 16 to 20 years* | Vaccinated: 199 Unvaccinated: 200 |
Prevalence ratio (Oral HPV 6/11/16/18) | 0.10 (0.01 to 0.97) | Age, circumcision and sex with women | Repeated cross‐sectional; *age at outcome |
| Closson 2020‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 35 years* | Vaccinated: 325 Unvaccinated: 725 |
Odds ratio (HPV 6/11/16/18) | 0.39 (0.19 to 0.83) | US birth, US citizenship, marital status, ethnicity, age, year of survey, education, health insurance, condom use, number of sexual partners, age at first sex, smoking history, binge‐drinking | Cross‐sectional; *age at outcome |
| Combita 2021‐COL | Gardasil (Merck quadrivalent) | Female, 18 to 25 years* | Vaccinated: 1986 Unvaccinated: 1287 |
Vaccine efficacy (HPV 6/11/16/18) | 62.6 (56.1 to 68.2) | Age, socioeconomic stratum, residence area, marital status, smoking, age of sexual debut, number of sexual partners, occasional sexual partners, contraceptive method and history of sexually transmitted diseases | Cross‐sectional; *age at outcome |
| Cummings 2012‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 17 years* | Vaccinated: 75 Unvaccinated: 150 |
Odds ratio (HPV 6/11/16/18) | 5.6 (1.9 to 16.5) | Matched with two historical controls from a previous cross‐sectional study by age at enrolment, clinic site and reported sexual activity at the time of enrolment | Cross‐sectional; *age at outcome |
| DeSisto 2024‐USA | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | MSM, 18 to 45 years | Vaccinated: 1249 Unvaccinated: 1553 |
Prevalence ratio (anal HPV 6/11/16/18) | 0.8 (0.68 to 0.95) | Adjusted for city, race/ethnicity and non‐9vHPV type prevalent infection | Cross‐sectional |
| De Souza 2023‐AUS | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female and male, 18 to 70 years | Vaccinated: 230 Unvaccinated: 671 |
Relative risk (oral; HPV 6/11/16/18) | 0.2 (0.03 to 1.49) | Unadjusted | Cross‐sectional |
| Dillner 2018‐EU | Gardasil (Merck quadrivalent) | Female, 18 to 50 years* | Vaccinated: 6299 Unvaccinated: 6494 |
Prevalence ratio (HPV 6/11/16/18; 2006‐8 vs 2012‐3) | 0.86 (0.79 to 0.95) | Unadjusted | Repeated cross‐sectional; *age at outcome |
| Enerly 2019‐NOR | Gardasil (Merck quadrivalent) | Female, 18 to 20 years* | Vaccinated: 239 Unvaccinated: 73 |
Prevalence ratio (HPV 6/11/16/18; ≥1 dose) | 0.04 (0.00 to 0.42) | Lifetime number of sexual partners, age at sexual debut and time since last sexual intercourse | Cross‐sectional; *age at outcome |
| Garland 2018‐AUS | Gardasil (Merck quadrivalent) | Female, 18 to 25 years* | Vaccinated: 620 Unvaccinated: 117 |
Prevalence ratio (HPV 6/11/16/18) | 0.22 (0.08 to 0.64) | Unadjusted | Cross‐sectional; *age at outcome |
| Goggin 2018‐CAN | Gardasil (Merck quadrivalent) | Female, 17 to 19 years* | Vaccinated: 577 Unvaccinated: 114 |
Prevalence ratio (long‐term; HPV 6/11/16/18) | 0.05 (0.01 to 0.24) | Unadjusted | Cross‐sectional; *age at outcome |
| Goggin 2018‐CAN | Gardasil (Merck quadrivalent) | Female, 20 to 22 years* | Vaccinated: 372 Unvaccinated: 194 |
Prevalence ratio (long‐term; HPV 6/11/16/18) | 0.15 (0.06 to 0.39) | Unadjusted | Cross‐sectional; *age at outcome |
| Goggin 2018‐CAN | Gardasil (Merck quadrivalent) | Female, 23 to 29 years* | Vaccinated: 87 Unvaccinated: 371 |
Prevalence ratio (long‐term; HPV 6/11/16/18) | 0.88 (0.45 to 1.75) | Unadjusted | Cross‐sectional; *age at outcome |
| Gonzalez 2020‐ARG | Gardasil (Merck quadrivalent) | Female, 15 to 17 years* | Vaccinated: 1224 Unvaccinated: 957 |
Odds ratio (HPV 6/11/16/18) | 0.24 (0.18 to 0.31) | Unadjusted | Cross‐sectional; *age at outcome |
| Heard 2017‐FRA | Gardasil (Merck quadrivalent) | Female, 18 to 25 years* | Vaccinated: 822 Unvaccinated: 1893 |
Prevalence ratio (HPV 6/11/16/18; ≥1 dose) | 0.04 (0.02 to 0.10) | Unadjusted | Cross‐sectional; *age at outcome |
| Hirth 2017‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 30 years* | Vaccinated: 668 Unvaccinated: 2372 |
Prevalence ratio (oral HPV 6/11/16/18) | 0.22 (0.05 to 0.92) | Unadjusted | Cross‐sectional; *age at outcome |
| Jacot‐Guillarmod 2017‐CHE | Gardasil (Merck quadrivalent) | Female, 18 years* | Vaccinated: 245 Unvaccinated: 77 |
Prevalence ratio (HPV 6/11/16/18) | 0.63 (0.16 to 2.45) | Unadjusted | Cross‐sectional; *age at outcome |
| Kahn 2016‐USA | Gardasil (Merck quadrivalent) | Female, 13 to 26 years* | Vaccinated: 286 Unvaccinated: 485 |
Odds ratio (HPV 6/11/16/18; 2006‐7 vs 2013‐4) | 0.18 (0.12 to 0.27) | Propensity score analysis adjusted for sociodemographic characteristics, gynaecologic history, sexual history and enrolment site | Repeated cross‐sectional; *age at outcome |
| Laake 2020‐NOR | Gardasil (Merck quadrivalent) | Female, 17 years* | Vaccinated: 6360 Unvaccinated: 5468 |
Relative risk (HPV 6/11/16/18) | 0.19 (0.15 to 0.24) | Unadjusted | Cross‐sectional; *age at outcome |
| Loenenbach 2023‐DEU | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female 20 to 25 years | Vaccinated: 348 Unvaccinated: 377 |
Prevalence ratio (HPV 6/11/16/18) | 0.5 (0.3 to 0.9) | Age, nationality, education, smoking, number of sexual partners, immunodeficiency and cancer screening | Cross‐sectional |
| Machalek 2018‐AUS | Gardasil (Merck quadrivalent) | Female, 18 to 35 years | Vaccinated: 381 Unvaccinated: 275 |
Prevalence ratio (HPV 6/11/16/18; 2005‐7 vs 2015) | 0.08 (0.03 to 0.20) | Age and smoking status | Repeated cross‐sectional; *age at outcome |
| Markowitz 2020‐USA | Gardasil (Merck quadrivalent) | Female, ≤ 18 years | Vaccinated: 2349 Unvaccinated: 1052 |
Prevalence ratio (HPV 6/11/16/18; 3 doses) | 0.06 (0.04 to 0.12) | Race/ethnicity and age at screening | Cross‐sectional |
| Markowitz 2020‐USA | Gardasil (Merck quadrivalent) | Female, ≤ 18 years | Vaccinated: 229 Unvaccinated: 1052 |
Prevalence ratio (HPV 6/11/16/18; 2 doses) | 0.05 (0.01 to 0.39) | Race/ethnicity and age at screening | Cross‐sectional |
| Markowitz 2020‐USA | Gardasil (Merck quadrivalent) | Female, ≤ 18 years | Vaccinated: 207 Unvaccinated: 1052 |
Prevalence ratio (HPV 6/11/16/18; 1 dose) | 0.06 (0.01 to 0.42) | Race/ethnicity and age at screening | Cross‐sectional |
| Markowitz 2020‐USA | Gardasil (Merck quadrivalent) | Female, > 18 years | Vaccinated: 261 Unvaccinated: 1052 |
Prevalence ratio (HPV 6/11/16/18; 3 doses) | 0.77 (0.44 to 1.36) | Race/ethnicity and age at screening | Cross‐sectional |
| Markowitz 2020‐USA | Gardasil (Merck quadrivalent) | Female, > 18 years | Vaccinated: 75 Unvaccinated: 1052 |
Prevalence ratio (HPV 6/11/16/18; 2 doses) | 0.36 (0.09 to 1.44) | Race/ethnicity and age at screening | Cross‐sectional |
| Markowitz 2020‐USA | Gardasil (Merck quadrivalent) | Female, > 18 years | Vaccinated: 96 Unvaccinated: 1052 |
Prevalence ratio (HPV 6/11/16/18; 1 dose) | 0.57 (0.21 to 1.53) | Race/ethnicity and age at screening | Cross‐sectional |
| Markowitz 2019‐USA | Gardasil (Merck quadrivalent) | Female, < 19 years | Vaccinated: 706 Unvaccinated: 4138 |
Prevalence ratio (HPV 6/11/16/18) | 0.1 (0.1 to 0.3) | Age, race, poverty, any chlamydia, HIV or pregnancy test | Repeated cross‐sectional |
| Markowitz 2019‐USA | Gardasil (Merck quadrivalent) | Female, ≥ 19 years | Vaccinated: 625 Unvaccinated: 4138 |
Prevalence ratio (HPV 6/11/16/18) | 0.7 (0.5 to 1.2) | Age, race, poverty, any chlamydia, HIV or pregnancy test | Repeated cross‐sectional |
| Markowitz 2019‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years | Vaccinated: 2059 Unvaccinated: 2057 |
Prevalence ratio (HPV 6/11/16/18; 2007 vs 2015‐2016) | 0.22 (0.17 to 0.29) | Unadjusted | Repeated cross‐sectional |
| Markowitz 2019‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years | Vaccinated: 2420 Unvaccinated: 2081 |
Prevalence ratio (HPV 6/11/16/18; 2007 vs 2015‐2016) | 0.62 (0.50 to 0.78) | Unadjusted | Repeated cross‐sectional |
| McDaniel 2020‐USA | Gardasil (Merck quadrivalent) | Female and male, 30 to 33 years* | Vaccinated: 46 Unvaccinated: 776 |
Prevalence ratio (oral HPV 6/11/16/18) | 0.62 (0.09 to 4.50) | Unadjusted | Cross‐sectional; *age at outcome |
| McGregor 2018‐AUS | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 142 Unvaccinated: 155 |
Prevalence ratio (HPV 6/11/16/18; 2005‐7 vs 2014‐5) | 0.06 (0.01 to 0.24) | Unadjusted | Repeated cross‐sectional; indigenous subgroup of population; *age at outcome |
| Napolitano 2024‐ITA | Not reported | Female and male, 18 to 30 years | Vaccinated: 490 Unvaccinated: 512 |
Prevalence ratio (HPV 6/11/16/18) | 0.70 (0.12 to 4.16) | Unadjusted | Cross‐sectional |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 17 years* | Vaccinated: 233 Unvaccinated: 244 |
Relative risk (cervicogenital HPV 6/11/16/18) | 0.2 (0.1 to 0.8) | Unadjusted | Cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 24 years* | Vaccinated: 241 Unvaccinated: 448 |
Relative risk (cervicogenital HPV 6/11/16/18) | 0.2 (0.1 to 0.3) | Unadjusted | Cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Male, 18 to 24 years* | Vaccinated: 52 Unvaccinated: 252 |
Relative risk (HPV 6/11/16/18) | 0.7 (0.1 to 5.4) | Unadjusted | Cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 24 years* | Vaccinated: 430 Unvaccinated: 679 |
Relative risk (oral HPV 6/11/16/18) | 0.1 (0.0 to 1.3) | Unadjusted | Cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 106 Unvaccinated: 1004 |
Difference in predicted probability (HPV 6/11/16/18; 1 dose) | ‐5.0 (‐5.6 to ‐4.5) | age, race/ethnicity, age at sexual debut, and lifetime number of male sexual partners. | Cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 126 Unvaccinated: 1004 |
Difference in predicted probability (HPV 6/11/16/18; 2 doses) | ‐1.7 (‐2.4 to ‐0.1) | Age, race/ethnicity, age at sexual debut and lifetime number of male sexual partners. | Cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 384 Unvaccinated: 1004 |
Difference in predicted probability (HPV 6/11/16/18; 3 doses) | ‐4.3 (‐4.6 to ‐4.0) | Age, race/ethnicity, age at sexual debut and lifetime number of male sexual partners | Cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 19 years* | Vaccinated: 666 Unvaccinated: 1363 |
Prevalence ratio (HPV 6/11/16/18; 2003‐6 vs 2015‐18) | 0.12 (0.06 to 0.26) | Race/ethnicity and ever having had sex | Repeated cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | Vaccinated: 368 Unvaccinated: 432 |
Prevalence ratio (HPV 6/11/16/18; 2003‐6 vs 2015‐18) | 0.19 (0.09 to 0.40 | Race/ethnicity and ever having had sex | Repeated cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years* | Vaccinated: 430 Unvaccinated: 403 |
Prevalence ratio (HPV 6/11/16/18; 2003‐6 vs 2015‐18) | 0.85 (0.50 to 1.46) | Race/ethnicity and ever having had sex | Repeated cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 34 years* | Vaccinated: 413 Unvaccinated: 389 |
Prevalence ratio (HPV 6/11/16/18; 2003‐6 vs 2015‐18) | 0.67 (0.37 to 1.21) | Race/ethnicity and ever having had sex | Repeated cross‐sectional; *age at outcome |
| Sankaranarayanan 2018‐IND | Gardasil (Merck quadrivalent) | Female, 10 to 18 years | Vaccinated: 818 Unvaccinated: 179 |
Odds ratio (oral HPV 6/11/16/18) | 0.6 (0.3 to 1.1) | Age at oral sample collection | Cross‐sectional |
| Sarr 2019‐CAN | Gardasil (Merck quadrivalent) | Female, > 18 years* | Vaccinated: 79 Unvaccinated: 956 |
Vaccine effectiveness (HPV 6/11/16/18) | 61.9% (‐23.5 to 92.6) | Age and number of new sexual partners in the last 12 months | Cross‐sectional; *age at outcome |
| Sayinzoga 2023‐RWA | Gardasil (Merck quadrivalent) | Female, 17 to 29 years | Vaccinated: 655 Unvaccinated: 2349 |
Vaccine effectiveness (HPV 6/11/16/18) | 70% (52 to 82) | Age, level of education, HIV status and lifetime number of sexual partners | Cross‐sectional |
| Schlecht 2016‐USA | Gardasil (Merck quadrivalent) | Female, 12 to 19 years* | Vaccinated: 957 Unvaccinated: 182 |
Incidence rate ratio (HPV 6/11/16/18) | 0.22 (0.13 to 0.37) | Exposure time, all concurrent types, current age, race/ethnicity, lifetime number of sex partners, history of anal sex, recent number of vaginal sex partners, age at first intercourse and sexual experience at time of vaccination | Repeated cross‐sectional; *age at outcome |
| Schlecht 2016‐USA | Gardasil (Merck quadrivalent) | Female, 12 to 19 years | Vaccinated: 957 Unvaccinated: 182 |
Incidence rate ratio (anal HPV 6/11/16/18) | 0.33 (0.18 to 0.69) | Exposure time, all concurrent types, current age, race/ethnicity, lifetime number of sex partners, history of anal sex, recent number of vaginal sex partners, age at first intercourse and sexual experience at time of vaccination | Repeated cross‐sectional; *age at outcome |
| Schlecht 2019‐USA | Gardasil (Merck quadrivalent) | Female, 13 to 21 years* | Vaccinated: 1067 Unvaccinated: 192 |
Odds ratio (oral HPV 6/11/16/18) | 0.20 (0.04 to 0.998) | Age, years since first sexual activity, concurrent cervical detection of quadrivalent HPV vaccine types | Repeated cross‐sectional; *age at outcome |
| Shilling 2021‐AUS | Gardasil (Merck quadrivalent) | Female, 18 to 35 years* | Vaccinated: 964 Unvaccinated: 348 |
Odds ratio (HPV 6/11/16/18) | 0.13 (0.05 to 0.32) | Age | Cross‐sectional; *age at outcome |
| Soderlund‐Strand 2014‐SWE | Gardasil (Merck quadrivalent) | Female, all ages* | Vaccinated: 532 Unvaccinated: 10,840 |
Prevalence ratio (HPV 6/11/16/18; 2008 vs 2013) | 0.49 (0.34 to 0.70) | Unadjusted | Repeated cross‐sectional; *age at outcome |
| Soderlund‐Strand 2014‐SWE | Gardasil (Merck quadrivalent) | Male, all ages* | Vaccinated: 1255 Unvaccinated: 11,009 |
Prevalence ratio (HPV 6/11/16/18; 2008 vs 2013) | 0.47 (0.32 to 0.68) | Unadjusted | Repeated cross‐sectional; *age at outcome |
| Spinner 2019‐USA | Gardasil (Merck quadrivalent) | Female, 13 to 26 years* | Vaccinated: 865 Unvaccinated: 715 |
Odds ratio (HPV 6/11/16/18) | 0.13 (0.08 to 0.22) | Enrolment site, age, race, history of STI, age at first intercourse, number of sexual partners, main partner being male, ever had anal sex, condom use and smoking history | Repeated cross‐sectional; *age at outcome |
| Subasinghe 2020‐AUS | Gardasil (Merck quadrivalent) | Female, 16 to 25 years* | Vaccinated: 218 Unvaccinated: 8 |
Risk ratio (HPV 6/11/16/18) | 0.02 (0.00 to 0.18) | Unadjusted | Cross‐sectional; *age at outcome |
| Tabrizi 2014‐AUS | Gardasil (Merck quadrivalent) | Female, 18 to 24 years* | Vaccinated: 909 Unvaccinated: 351 |
Vaccine effectiveness (HPV 6/11/16/18) | 86% (71% to 93%) | Age, hormonal contraceptive use, education, country of birth and number of sexual partners in the past 12 months | Repeated cross‐sectional; *age at outcome |
| Tabrizi 2014‐AUS | Gardasil (Merck quadrivalent) | Female, 18 to 24 years* | Vaccinated: 909 Unvaccinated: 351 |
Prevalence ratio (HPV 6/11/16/18; 2005‐2007 vs 2010‐2012) | 0.22 (0.16 to 0.31) | Age, hormonal contraceptive use | Repeated cross‐sectional; *age at outcome |
| Wendland 2021‐BRA | Gardasil (Merck quadrivalent) | Female, 16 to 25 years* | Vaccinated: 677 Unvaccinated: 5268 |
Risk ratio (HPV 6/11/16/18) | 0.43 (0.33 to 0.58) | Unadjusted | Cross‐sectional; *age at outcome |
| Widdice 2019‐USA | Gardasil (Merck quadrivalent) | Male, 13 to 26 years* | Vaccinated: 143 Unvaccinated: 471 |
Risk ratio (HPV 6/11/16/18; 3 doses) | 0.85 (0.60 to 1.20) | Unadjusted | Cross‐sectional; *age at outcome |
| Widdice 2019‐USA | Gardasil (Merck quadrivalent) | Male, 13 to 26 years* | Vaccinated: 37 Unvaccinated: 471 |
Risk ratio (HPV 6/11/16/18; 2 doses) | 1.06 (0.61 to 1.84) | Unadjusted | Cross‐sectional; *age at outcome |
| Widdice 2019‐USA | Gardasil (Merck quadrivalent) | Male, 13 to 26 years* | Vaccinated: 58 Unvaccinated: 471 |
Risk ratio (HPV 6/11/16/18; 1 dose) | 0.74 (0.43 to 1.30) | Unadjusted | Cross‐sectional; *age at outcome |
| Winer 2021‐USA | Gardasil (Merck quadrivalent) | Male, 11 to 18 years | Vaccinated: 348 Unvaccinated: 339 |
Prevalence ratio (penile HPV 6/11/16/18) | 0.15 (0.04 to 0.62) | Age, history of ever taking PrEP for HIV prevention, HIV status, lifetime number of sex partners | Cross‐sectional |
| Winer 2021‐USA | Gardasil (Merck quadrivalent) | Male, 19 to 26 years | Vaccinated: 348 Unvaccinated: 339 |
Prevalence ratio (penile HPV 6/11/16/18) | 0.80 (0.52 to 1.22) | Age, history of ever taking PrEP for HIV prevention, HIV status, lifetime number of sex partners | Cross‐sectional |
| Winer 2021‐USA | Gardasil (Merck quadrivalent) | Male, 11 to 18 years | Vaccinated: 348 Unvaccinated: 339 |
Prevalence ratio (anal and/or oral HPV 6/11/16/18) | 0.41 (0.24 to 0.57) | Age, history of ever taking PrEP for HIV prevention, HIV status, lifetime number of sex partners | Cross‐sectional |
| Winer 2021‐USA | Gardasil (Merck quadrivalent) | Male, 19 to 26 years | Vaccinated: 348 Unvaccinated: 339 |
Prevalence ratio (anal and/or oral HPV 6/11/16/18) | 0.82 (0.67 to 0.98) | Age, history of ever taking PrEP for HIV prevention, HIV status, lifetime number of sex partners | Cross‐sectional |
| Wissing 2019‐CAN | Gardasil (Merck quadrivalent) | Female, 18 to 26 years* | Vaccinated: 63 Unvaccinated: 434 |
Odds ratio (HPV 6/11/16/18) | 0.14 (0.04 to 0.51) | Age, race, smoking status, age at first coitus, number of lifetime sex partners, same‐sex partners and/or concurrent sex partners, condom use, average frequency of coitus and duration of the sexual relationship | Cross‐sectional; *age at outcome |
| Khoo 2022‐MYS | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 18 to 24 years | Vaccinated: 75 Unvaccinated: 1135 |
Prevalence change (HPV 6/11/16/18) | ‐86.5% (‐97.5% to ‐27.5%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Khoo 2022‐MYS | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 35 to 45 years | Vaccinated: 75 Unvaccinated: 1135 |
Prevalence change (HPV 6/11/16/18) | ‐40.5% (‐74.3% to 37.9%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
HPV: human papillomavirus; MSM: men who have sex with men; PrEP: pre‐exposure prophylaxis; STI: sexually transmitted infection
68. Secondary clinical outcomes effect estimates: prevalent HPV 31/33/45/52/58 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Abel 2021‐USA | Gardasil (Merck quadrivalent) | Female and male, 18 to 36 years* | Vaccinated: 198 Unvaccinated: 4801 |
Prevalence ratio (HPV 31/33/45/52/58; 1 dose) | 0.90 (0.12 to 6.58) | Unadjusted | Cross‐sectional; *age at outcome |
| Abel 2021‐USA | Gardasil (Merck quadrivalent) | Female and male, 18 to 36 years* | Vaccinated: 799 Unvaccinated: 4801 |
Prevalence ratio (HPV 31/33/45/52/58; 2 or 3 doses) | 1.34 (0.55 to 3.22) | Unadjusted | Cross‐sectional; *age at outcome |
| DeSisto 2024‐USA | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | MSM, 18 to 45 years | Vaccinated: 1249 Unvaccinated: 1553 |
Prevalence ratio (anal HPV 31/33/45/52/58) | 0.73 (0.62 to 0.85) | Adjusted for city, race/ethnicity and non‐9vHPV type prevalent infection. | Cross‐sectional |
| Mesher 2018‐GBR | Cervarix (GSK bivalent) | Female, 12 to 15 years | Vaccinated: 1176 Unvaccinated: 117 |
Vaccine effectiveness (HPV 31/33/45/52/58) | 16.4% (‐30.9 to 46.5) | Age, testing venue type and chlamydia positivity | Repeated cross‐sectional |
| Mesher 2018‐GBR | Cervarix (GSK bivalent) | Female, 16 to 18 years | Vaccinated: 614 Unvaccinated: 289 |
Vaccine effectiveness (HPV 31/33/45/52/58) | 20.6% (−3.5 to 39.1) | Age, testing venue type and chlamydia positivity | Repeated cross‐sectional |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 14 to 19 years* | Vaccinated: 666 Unvaccinated: 1363 |
Prevalence ratio (HPV 31/33/45/52/58; 2003‐6 vs 2015‐18) | 0.35 (0.18 to 0.65 | Race/ethnicity and ever having had sex | Repeated cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 20 to 24 years* | Vaccinated: 368 Unvaccinated: 432 |
Prevalence ratio (HPV 31/33/45/52/58; 2003‐6 vs 2015‐18) | 0.62 (0.38 to 1.01 | Race/ethnicity and ever having had sex | Repeated cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 25 to 29 years* | Vaccinated: 430 Unvaccinated: 403 |
Prevalence ratio (HPV 31/33/45/52/58; 2003‐6 vs 2015‐18) | 0.99 (0.58 to 1.67 | Race/ethnicity and ever having had sex | Repeated cross‐sectional; *age at outcome |
| Rosenblum 2021‐USA | Gardasil (Merck quadrivalent) | Female, 30 to 34 years* | Vaccinated: 413 Unvaccinated: 389 |
Prevalence ratio (HPV 31/33/45/52/58; 2003‐6 vs 2015‐18) | 0.68 (0.37 to 1.27 | Race/ethnicity and ever having had sex | Repeated cross‐sectional; *age at outcome |
| Spinner 2019‐USA | Gardasil (Merck quadrivalent) | Female, 13 to 26 years* | Vaccinated: 865 Unvaccinated: 715 |
Odds ratio (HPV 31/33/45/52/58) | 0.26 (0.16 to 0.42) | Enrolment site, age, race, history of STI, age at first intercourse, number of sexual partners, main partner being male, ever had anal sex, condom use and smoking history | Repeated cross‐sectional; *age at outcome |
| Tanton 2017‐GBR | Cervarix (GSK bivalent) | Female, 18 to 20 years* | Vaccinated: 84 Unvaccinated: 265 |
Prevalence ratio (HPV 31/33/45/52/58; 1999‐2001 vs 2010‐2012) | 1.19 (0.69 to 2.05) | Age | Repeated cross‐sectional; *age at outcome |
| Khoo 2022‐MYS | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 18 to 24 years | Vaccinated: 75 Unvaccinated: 1135 |
Prevalence change (HPV 31/33/45/52/58) | 21.8% (‐73.1% to 45.2%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
| Khoo 2022‐MYS | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | Female, 35 to 45 years | Vaccinated: 75 Unvaccinated: 1135 |
Prevalence change % (HPV 31/33/45/52/58) | ‐38.2% (‐69.9% to 26.9%) | Unadjusted | Pre‐ vs post‐vaccine introduction |
HPV: human papillomavirus; MSM: men who have sex with men; STI: sexually transmitted infection
69. Secondary clinical outcomes effect estimates: prevalent HPV 6/11/16/18/31/33/45/52/58 infection.
| Study | Vaccine | Population (sex, age at vaccination) | Sample size | Effect measure (time period) | Effect estimate | Adjustment factors | Notes |
| Berenson 2021‐USA | Gardasil (Merck quadrivalent) | Female and male, 18 to 59 years* | Vaccinated: 939 Unvaccinated: 8498 |
Risk ratio (oral HPV 6/11/16/18/31/33/45/52/58) | 0.60 (0.34 to 1.08) | Unadjusted | Cross‐sectional; *age at outcome |
| Berenson 2021‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 59 years* | Vaccinated: 723 Unvaccinated: 4164 |
Risk ratio (oral HPV 6/11/16/18/31/33/45/52/58) | 0.90 (0.35 to 2.30) | Unadjusted | Cross‐sectional; *age at outcome |
| Berenson 2021‐USA | Gardasil (Merck quadrivalent) | Male, 18 to 59 years* | Vaccinated: 216 Unvaccinated: 4334 |
Risk ratio (oral HPV 6/11/16/18/31/33/45/52/58) | 0.94 (0.45 to 1.98) | Unadjusted | Cross‐sectional; *age at outcome |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male ≤ 23 years at vaccination | Vaccinated: 118 Unvaccinated: 349 |
Prevalence ratio (HPV 6/11/16/18/31/33/45/52/58) | 0.76 (0.56 to 1.02) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male > 23 years at vaccination | Vaccinated: 112 Unvaccinated: 349 |
Prevalence ratio (HPV 6/11/16/18/31/33/45/52/58) | 0.69 (0.49 to 0.96) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male, 16 to 30 years* | Vaccinated: 136 Unvaccinated: 349 |
Prevalence ratio (HPV 6/11/16/18/31/33/45/52/58; 3 doses) | 0.70 (0.52 to 0.94) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional; *age at outcome |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male, 16 to 30 years* | Vaccinated: 184 Unvaccinated: 349 |
Prevalence ratio (HPV 6/11/16/18/31/33/45/52/58; 2 doses) | 0.76 (0.59 0.98) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional; *age at outcome |
| Chambers 2022‐CAN | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Male 16 to 30 years* | Vaccinated: 241 Unvaccinated: 349 |
Prevalence ratio (HPV 6/11/16/18/31/33/45/52/58; at least 1 dose) | 0.72 (0.57 to 0.91) | Age group, city, education, lifetime smoking history, lifetime history of STIs (excluding HIV and anogenital warts) and number of condomless receptive anal sex encounters in the past 6 months | Cross‐sectional; *age at outcome |
| Chow 2019‐AUS | Gardasil (Merck quadrivalent) | Male, 17 to 19 years* | Vaccinated: 146 Unvaccinated: 152 |
Prevalence ratio (Penile HPV 6/11/16/18/31/33/45/52/58; 2014‐5 vs 2016‐7) | 0.58 (0.22 to 1.51) | Age and source of recruitment | Repeated cross‐sectional; *age at outcome |
| De Souza 2023‐AUS | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | Female and male, 18 to 70 years | Vaccinated: 230 Unvaccinated: 671 |
Relative risk (oral; HPV 6/11/16/18/31/33/45/52/58) | 0.25 (0.06 to 1.07) | Unadjusted | Cross‐sectional |
| Hirth 2017‐USA | Gardasil (Merck quadrivalent) | Female, 18 to 30 years* | Vaccinated: 668 Unvaccinated: 2372 |
Prevalence ratio (oral HPV 6/11/16/18/31/33/45/52/58) | 0.53 (0.23 to 1.25) | Unadjusted | Cross‐sectional; *age at outcome |
| Laake 2020‐NOR | Gardasil (Merck quadrivalent) | Female, 17 years* | Vaccinated: 6360 Unvaccinated: 5468 |
Relative risk (HPV 6/11/16/18/31/33/45/52/58) | 0.28 (0.24 to 0.34) | Unadjusted | Cross‐sectional; *age at outcome |
| Latsuzbaia 2019‐LUX | Gardasil (Merck quadrivalent) | Female, 18 to 29 years* | Vaccinated: 216 Unvaccinated: 232 |
Odds ratio (HPV 6/11/16/18/31/33/45/52/58) | 0.81 (0.47 to 1.40) | Number of lifetime sexual partners, last partnership duration and age | Cross‐sectional; *age at outcome |
| Latsuzbaia 2019‐LUX | Cervarix (GSK bivalent) | Female, 18 to 29 years* | Vaccinated: 216 Unvaccinated: 131 |
Odds ratio (HPV 6/11/16/18/31/33/45/52/58) | 0.29 (0.13 to 0.67) | Number of lifetime sexual partners, last partnership duration and age | Cross‐sectional; *age at outcome |
| Napolitano 2024‐ITA | Not reported | Female and male, 18 to 30 years | Vaccinated: 490 Unvaccinated: 512 |
Prevalence ratio (HPV 6/11/16/18/31/33/45/52/58) | 0.47 (0.15 to 1.51) | Unadjusted | Cross‐sectional |
| Schlecht 2016‐USA | Gardasil (Merck quadrivalent) | Female, 12 to 19 years | Vaccinated: 957 Unvaccinated: 182 |
Incidence rate ratio (HPV 6/11/16/18/31/33/45/52/58) | 0.97 (0.61 to 1.54) | Exposure time, all concurrent types, current age, race/ethnicity, lifetime number of sex partners, history of anal sex, recent number of vaginal sex partners, age at first intercourse and sexual experience at time of vaccination | Repeated cross‐sectional; *age at outcome |
| Schlecht 2016‐USA | Gardasil (Merck quadrivalent) | Female, 12 to 19 years | Vaccinated: 957 Unvaccinated: 182 |
Incidence rate ratio (anal HPV 6/11/16/18/31/33/45/52/58) | 0.64 (0.35 to 1.19) | Exposure time, all concurrent types, current age, race/ethnicity, lifetime number of sex partners, history of anal sex, recent number of vaginal sex partners, age at first intercourse and sexual experience at time of vaccination | Repeated cross‐sectional; *age at outcome |
| Spinner 2019‐USA | Gardasil (Merck quadrivalent) | Female, 13 to 26 years* | Vaccinated: 865 Unvaccinated: 715 |
Odds ratio (HPV 6/11/16/18/31/33/45/52/58) | 0.18 (0.12 to 0.26) | Enrolment site, age, race, history of STI, age at first intercourse, number of sexual partners, main partner being male, ever had anal sex, condom use and smoking history | Repeated cross‐sectional; *age at outcome |
| Woestenberg 2020‐NLD | Cervarix (GSK bivalent) | Female, 16 to 24 years* | Vaccinated: 357 Unvaccinated: 191 |
Vaccine effectiveness (anal HPV 6/11/16/18/31/33/45/52/58) | 33.5 (‐0.3 to 55.9) | Age, education level, history of anal sex, number of sex partners in the past 6 months, sexually transmitted infection‐related symptoms and use of hormonal contraceptives | Cross‐sectional; *age at outcome |
HPV: human papillomavirus; STI: sexually transmitted infection
70. Risk of bias summary: prevalent HPV infection.
| Study | Confounding | Selection | Classification of interventions | Deviations from intended interventions | Missing data | Measurement of outcomes | Selection of reported result | Overall risk of bias |
| Prevalent HPV 16/18 infection | ||||||||
| Batmunkh 2020‐MNG | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Batmunkh 2019‐MNG | Serious | Moderate | Moderate | Low | Low | Moderate | Low | Serious |
| Bobadilla 2024‐PAR | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Bogaards 2019‐NLD | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Carnalla 2021‐MEX | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Carozzi 2018‐ITA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Combita 2021‐COL | Serious | Low | Moderate | Low | Moderate | Moderate | Low | Serious |
| Cummings 2012‐USA | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
| Delere 2014‐DEU | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Enerly 2019‐NOR | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Feder 2019‐USA | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Gonzalez 2020‐ARG | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Heard 2017‐FRA | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Hiramatsu 2021‐JPN | Critical | Serious | Low | Low | Moderate | Low | Low | Critical |
| Hirth 2017‐USA | Critical | Low | Moderate | Low | Moderate | Low | Low | Critical |
| Jeannot 2018‐CHE | Serious | Low | Moderate | Low | Moderate | Moderate | Low | Serious |
| Kahn 2016‐USA | Moderate | Moderate | Low | Low | Low | Low | Low | Moderate |
| Kitamura 2023‐JPN | Serious | Low | Serious | Low | Moderate | Low | Low | Serious |
| Kreimer 2011‐CRI | Serious | Moderate | Moderate | Low | Moderate | Low | Low | Serious |
| Kudo 2019‐JPN | Serious | Low | Low | Low | Serious | Low | Low | Serious |
| Kumakech 2016‐UGA | Critical | Low | Low | Low | Moderate | Low | Low | Critical |
| Laake 2020‐NOR | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Latsuzbaia 2019‐LUX | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Lee 2022‐THA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Lehtinen 2017a‐FIN | Critical | Moderate | Low | Low | Low | Moderate | Low | Critical |
| Loenenbach 2023‐DEU | Serious | Low | Moderate | Low | Moderate | Moderate | Low | Serious |
| Lynge 2020‐DNK | Critical | Serious | Serious | Low | Moderate | Low | Low | Critical |
| Markowitz 2019‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Mehanna 2019‐GBR | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Mesher 2018‐GBR | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Napolitano 2024‐ITA | Critical | Low | Moderate | Low | Moderate | Low | Low | Critical |
| Nilyanimit 2024‐THA | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Palmer 2019‐GBR | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Purrinos‐Hermida 2018‐ESP | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Reyburn 2023‐FJI | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Saeki 2024‐JPN | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Saldanha 2020‐PRT | Critical | Serious | Serious | Low | Low | Low | Low | Critical |
| Sankaranarayanan 2018‐IND | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Sarr 2019‐CAN | Serious | Low | Moderate | Low | Low | Low | Low | Serious |
| Tanton 2017‐GBR | Serious | Low | Moderate | Low | Low | Low | Low | Serious |
| Van Eer 2021‐NLD | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Wendland 2021‐BRA | Critical | Low | Moderate | Low | Low | Low | Low | Critical |
| Woestenberg 2020‐NLD | Serious | Serious | Moderate | Low | Low | Low | Low | Serious |
| Wright 2019‐USA | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Huyghe 2023‐BEL | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Khoo 2022‐MYS | Critical | Low | Serious | Low | Moderate | Low | Low | Critical |
| Rebolj 2022‐GBR | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Saeki 2024‐JPN | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Prevalent HPV 6/11/16/18 infection | ||||||||
| Ahrlund‐Richter 2019‐SWE | Critical | Low | Low | Low | Serious | Low | Low | Critical |
| Abel 2021‐USA | Serious | Low | Moderate | Low | Moderate | Low | Low | Serious |
| Balgovind 2024‐AUS | Critical | Low | Moderate | Low | Moderate | Low | Low | Critical |
| Baussano 2021‐RWA/BTN | Serious | Moderate | Moderate | Low | Moderate | Low | Low | Serious |
| Baussano 2020‐BTN | Serious | Low | Serious | Low | Low | Low | Low | Serious |
| Berenson 2021‐USA | Critical | Low | Moderate | Low | Moderate | Low | Low | Critical |
| Bobadilla 2024‐PAR | Critical | Moderate | Moderate | Low | Low | Low | Low | Critical |
| Carozzi 2018‐ITA | Serious | Low | Low | Low | Low | Low | Low | Serious |
| Chambers 2022‐CAN | Serious | Moderate | Moderate | Low | Moderate | Low | Low | Serious |
| Chow 2017‐AUS | Critical | Serious | Serious | Moderate | Moderate | Low | Low | Critical |
| Chow 2019‐AUS | Serious | Serious | Serious | Moderate | Low | Low | Low | Serious |
| Chow 2021a‐AUS | Serious | Moderate | Serious | Low | Moderate | Low | Low | Serious |
| Closson 2020‐USA | Moderate | Low | Moderate | Low | Moderate | Low | Low | Moderate |
| Combita 2021‐COL | Serious | Low | Moderate | Low | Moderate | Moderate | Low | Serious |
| Cummings 2012‐USA | Serious | Moderate | Serious | Low | Low | Low | Low | Serious |
| DeSisto 2024‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| De Souza 2023‐AUS | Critical | Low | Low | Low | Moderate | Low | Low | Critical |
| Dillner 2018‐EU | Critical | Moderate | Serious | Low | Low | Low | Low | Critical |
| Enerly 2019‐NOR | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Garland 2018‐AUS | Critical | Moderate | Low | Low | Moderate | Low | Low | Critical |
| Gonzalez 2020‐ARG | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Heard 2017‐FRA | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Hirth 2017‐USA | Critical | Low | Moderate | Low | Moderate | Low | Low | Critical |
| Jacot‐Guillarmod 2017‐CHE | Critical | Moderate | Moderate | Low | Moderate | Low | Low | Critical |
| Kahn 2016‐USA | Moderate | Moderate | Low | Low | Low | Low | Low | Moderate |
| Laake 2020‐NOR | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Loenenbach 2023‐DEU | Serious | Low | Moderate | Low | Moderate | Moderate | Low | Serious |
| Machalek 2018‐AUS | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Markowitz 2020‐USA | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Markowitz 2019‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| McDaniel 2020‐USA | Critical | Low | Moderate | Low | Low | Low | Low | Critical |
| McGregor 2018‐AUS | Critical | Serious | Serious | Low | Low | Low | Low | Critical |
| Napolitano 2024‐ITA | Critical | Low | Moderate | Low | Moderate | Low | Low | Critical |
| Rosenblum 2021‐USA | Moderate | Low | Moderate | Low | Low | Low | Low | Moderate |
| Sankaranarayanan 2018‐IND | Serious | Low | Low | Low | Moderate | Low | Low | Serious |
| Sarr 2019‐CAN | Serious | Low | Moderate | Low | Low | Low | Low | Serious |
| Sayinzoga 2023‐RWA | Serious | Low | Moderate | Low | Low | Low | Low | Serious |
| Schlecht 2016‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Schlecht 2019‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Shilling 2021‐AUS | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Soderlund‐Strand 2014‐SWE | Critical | Low | Serious | Low | Low | Low | Low | Critical |
| Spinner 2019‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Subasinghe 2020‐AUS | Critical | Serious | Low | Low | Serious | Low | Low | Critical |
| Tabrizi 2014‐AUS | Critical | Moderate | Low | Low | Low | Low | Low | Critical |
| Wendland 2021‐BRA | Critical | Low | Moderate | Low | Low | Low | Low | Critical |
| Widdice 2019‐USA | Critical | Moderate | Low | Low | Moderate | Low | Low | Critical |
| Winer 2021‐USA | Serious | Moderate | Moderate | Low | Moderate | Low | Low | Serious |
| Wissing 2019‐CAN | Serious | Moderate | Moderate | Low | Low | Low | Low | Serious |
| Khoo 2022‐MYS | Critical | Low | Serious | Low | Moderate | Low | Low | Critical |
| Prevalent HPV 31/33/45/52/58 infection | ||||||||
| Abel 2021‐USA | Serious | Low | Moderate | Low | Moderate | Low | Low | Serious |
| DeSisto 2024‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Mesher 2018‐GBR | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Rosenblum 2021‐USA | Moderate | Low | Moderate | Low | Low | Low | Low | Moderate |
| Spinner 2019‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Tanton 2017‐GBR | Serious | Low | Moderate | Low | Low | Low | Low | Serious |
| Khoo 2022‐MYS | Critical | Low | Serious | Low | Moderate | Low | Low | Critical |
| Prevalent HPV 6/11/16/18/31/33/45/52/58 infection | ||||||||
| Berenson 2021‐USA | Critical | Low | Moderate | Low | Moderate | Low | Low | Critical |
| Chambers 2022‐CAN | Serious | Moderate | Moderate | Low | Moderate | Low | Low | Serious |
| Chow 2019‐AUS | Serious | Serious | Moderate | Moderate | Low | Low | Low | Serious |
| De Souza 2023‐AUS | Critical | Low | Low | Low | Moderate | Low | Low | Critical |
| Hirth 2017‐USA | Serious | Low | Moderate | Low | Moderate | Low | Low | Serious |
| Laake 2020‐NOR | Critical | Low | Low | Low | Low | Low | Low | Critical |
| Latsuzbaia 2019‐LUX | Serious | Moderate | Low | Low | Moderate | Low | Low | Serious |
| Napolitano 2024‐ITA | Critical | Low | Moderate | Low | Moderate | Low | Low | Critical |
| Schlecht 2016‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Spinner 2019‐USA | Serious | Moderate | Low | Low | Low | Low | Low | Serious |
| Woestenberg 2020‐NLD | Serious | Serious | Moderate | Low | Low | Low | Low | Serious |
HPV: human papillomavirus
HPV 16/18
Forty‐six studies were included that reported on prevalent HPV 16/18 infection following HPV vaccination (Batmunkh 2020‐MNG; Bobadilla 2024‐PAR; Bogaards 2019‐NLD; Carnalla 2021‐MEX; Carozzi 2018‐ITA; Combita 2021‐COL; Cummings 2012‐USA; Delere 2014‐DEU; Enerly 2019‐NOR; Feder 2019‐USA; Gonzalez 2020‐ARG; Heard 2017‐FRA; Hiramatsu 2021‐JPN; Hirth 2017‐USA; Huyghe 2023‐BEL; Jeannot 2018‐CHE; Kahn 2016‐USA; Khoo 2022‐MYS; Kitamura 2023‐JPN; Kreimer 2011‐CRI; Kudo 2019‐JPN; Kumakech 2016‐UGA; Laake 2020‐NOR; Latsuzbaia 2019‐LUX; Lee 2022‐THA; Lehtinen 2017a‐FIN; Loenenbach 2023‐DEU; Lynge 2020‐DNK; Markowitz 2019‐USA; Mehanna 2019‐GBR; Mesher 2018‐GBR; Napolitano 2024‐ITA; Nilyanimit 2024‐THA; Palmer 2019‐GBR; Purrinos‐Hermida 2018‐ESP; Rebolj 2022‐GBR; Reyburn 2023‐FJI; Saeki 2024‐JPN; Saldanha 2020‐PRT; Sankaranarayanan 2018‐IND; Sarr 2019‐CAN; Tanton 2017‐GBR; Van Eer 2021‐NLD; Wendland 2021‐BRA; Woestenberg 2020‐NLD; Wright 2019‐USA).
The type of effect estimate reported varied across studies, but almost all studies reported a reduction in HPV genital 16/18 infection with HPV vaccine. Three studies reported on oral HPV 16/18 infection (Hirth 2017‐USA; Mehanna 2019‐GBR; Sankaranarayanan 2018‐IND). All three studies reported a reduction in prevalence following HPV vaccination but had confidence intervals that included no effect. One study reported a reduction of anal HPV 16/18 infection with a vaccine effectiveness of 89.9% (63.0% to 97.2%) (Woestenberg 2020‐NLD).
Four studies reported on the effect of two doses or one dose of HPV vaccine on HPV 16/18 infection (Batmunkh 2020‐MNG; Kreimer 2011‐CRI; Palmer 2019‐GBR; Reyburn 2023‐FJI). The studies reported a reduction in HPV 16/18 infection following vaccination with two doses or one dose.
HPV 6/11/16/18
Forty‐nine studies were included that reported on prevalent HPV 6/11/16/18 infection following HPV vaccination (Ahrlund‐Richter 2019‐SWE; Abel 2021‐USA; Balgovind 2024‐AUS; Baussano 2021‐RWA/BTN; Baussano 2020‐BTN; Berenson 2021‐USA; Bobadilla 2024‐PAR; Carozzi 2018‐ITA; Chambers 2022‐CAN; Chow 2017‐AUS; Chow 2019‐AUS; Chow 2021a‐AUS; Closson 2020‐USA; Combita 2021‐COL; Cummings 2012‐USA; De Souza 2023‐AUS; DeSisto 2024‐USA; Dillner 2018‐EU; Enerly 2019‐NOR; Garland 2018‐AUS; Goggin 2018‐CAN; Gonzalez 2020‐ARG; Heard 2017‐FRA; Hirth 2017‐USA; Jacot‐Guillarmod 2017‐CHE; Kahn 2016‐USA; Khoo 2022‐MYS; Laake 2020‐NOR; Machalek 2018‐AUS; Markowitz 2020‐USA; Markowitz 2019‐USA; McDaniel 2020‐USA; McGregor 2018‐AUS; Napolitano 2024‐ITA; Rosenblum 2021‐USA; Sankaranarayanan 2018‐IND; Sarr 2019‐CAN; Sayinzoga 2023‐RWA; Schlecht 2016‐USA; Schlecht 2019‐USA; Shilling 2021‐AUS; Soderlund‐Strand 2014‐SWE; Spinner 2019‐USA; Subasinghe 2020‐AUS; Tabrizi 2014‐AUS; Wendland 2021‐BRA; Widdice 2019‐USA; Winer 2021‐USA; Wissing 2019‐CAN).
The type of effect estimate reported varied across studies, but almost all studies reported a reduction in genital HPV 6/11/16/18 infection with HPV vaccine. Nine studies reported on oral HPV 6/11/16/18 (Berenson 2021‐USA; Chow 2021a‐AUS; De Souza 2023‐AUS; Hirth 2017‐USA; McDaniel 2020‐USA; Rosenblum 2021‐USA; Sankaranarayanan 2018‐IND; Schlecht 2019‐USA; Winer 2021‐USA) and all except one study (McDaniel 2020‐USA) reported a reduced prevalence following vaccination. One study reported a decrease in oral HPV prevalence in males but not in females (Berenson 2021‐USA). Three studies reported that anal HPV 6/11/16/18 prevalence in males decreased with HPV vaccination (Chambers 2022‐CAN; Chow 2021a‐AUS; Winer 2021‐USA). One study reported the effect was more pronounced in males receiving the vaccine at a younger age (Chambers 2022‐CAN). One study reported a reduction in anal HPV 6/11/16/18 prevalence in females following HPV vaccination (Schlecht 2016‐USA). Three studies reported a reduction in penile HPV 6/11/16/18 prevalence in males following vaccination (Chow 2019‐AUS; Chow 2021a‐AUS; Winer 2021‐USA).
Five studies reported on the effect of two doses or one dose of HPV vaccine on HPV 6/11/16/18 infection (Abel 2021‐USA; Chambers 2022‐CAN; Markowitz 2020‐USA; Rosenblum 2021‐USA; Widdice 2019‐USA). Three studies reported no effect of two doses or one dose (Abel 2021‐USA; Chambers 2022‐CAN; Widdice 2019‐USA), while two studies reported a reduced prevalence following at least one dose (Markowitz 2020‐USA; Rosenblum 2021‐USA). One study reported that effectiveness varied according to age at first vaccination (Markowitz 2020‐USA).
HPV 31/33/45/52/58
Seven studies were included that reported on prevalent HPV 31/33/45/52/58 infection following HPV vaccination (Abel 2021‐USA; DeSisto 2024‐USA; Khoo 2022‐MYS; Mesher 2018‐GBR; Rosenblum 2021‐USA; Spinner 2019‐USA; Tanton 2017‐GBR). Three studies reported a reduction in HPV 31/33/45/52/58 infection following HPV vaccination (DeSisto 2024‐USA; Rosenblum 2021‐USA; Spinner 2019‐USA). Only one of these studies reported on the effectiveness of the 9‐valent HPV vaccine, which includes these HPV subtypes (DeSisto 2024‐USA). The prevalence ratio for anal HPV 31/33/45/52/58 infection in men who have sex with men was 0.73 (95% CI 0.62 to 0.85) following HPV vaccination.
HPV 6/11/16/18/31/33/45/52/58
Eleven studies were included that reported on prevalent HPV 6/11/16/18/31/33/45/52/58 infection following HPV vaccination (Berenson 2021‐USA; Chambers 2022‐CAN; Chow 2019‐AUS; De Souza 2023‐AUS; Hirth 2017‐USA; Laake 2020‐NOR; Latsuzbaia 2019‐LUX; Napolitano 2024‐ITA; Schlecht 2016‐USA; Spinner 2019‐USA; Woestenberg 2020‐NLD). Five studies reported a reduction of prevalence following HPV vaccination (Chambers 2022‐CAN; De Souza 2023‐AUS; Laake 2020‐NOR; Latsuzbaia 2019‐LUX; Spinner 2019‐USA).
Discussion
Summary of main results
We included 225 studies from 347 records in this review. We included 86 cohort studies, four case‐control studies, 46 cross‐sectional studies, 69 pre‐post vaccine introduction studies, five RCT extensions and two self‐controlled case series. Thirteen additional studies reported on more than one type of analysis. Of the included studies, 177 reported on only females, 11 only males, and 37 a combination of males and females. Risk of bias ranged from overall low risk of bias in the self‐controlled case series to moderate, serious and critical risk of bias in the other study designs.
Clinical outcomes
There was moderate‐certainty evidence that HPV vaccination reduces the incidence of cervical cancer. Meta‐analysis of cohort studies with effect estimates adjusted for confounding showed a reduced risk of cervical cancer following HPV vaccination (RR 0.37, 95% CI 0.25 to 0.56). Six studies of different designs reported no cases of cervical cancer in the HPV vaccine groups. Eight pre‐post vaccine introduction studies reported a reduction in cervical cancer incidence following HPV vaccine introduction.
There was moderate‐certainty evidence that HPV vaccination reduces the incidence of CIN3+. Eleven of 12 cohort studies reported a reduced risk of CIN3+ following HPV vaccination. Eight studies of different designs reported a decrease in CIN3+ incidence in HPV vaccinated participants. One other study reported no difference in the risk of CIN3+. Three pre‐post vaccine introduction studies reported a decrease in CIN3+ incidence following HPV vaccine introduction.
There was low‐certainty evidence that HPV vaccination reduces the incidence of vaginal cancer, penile cancer, head and neck cancer, VaIN and AIN.
There was only very low‐certainty evidence on the effect of HPV vaccination on the incidence of AIS, vulval cancer, anal cancer in males or females, and VIN.
There was moderate‐certainty evidence that HPV vaccination reduces the incidence of CIN3. One cohort study and a case‐control study reported a reduced risk of CIN3 following HPV vaccination. Two cross‐sectional studies reported no difference in the risk of CIN3 in vaccinated and unvaccinated participants. Four pre‐post vaccine introduction studies reported a reduction in CIN3 incidence following HPV introduction and one study reported an increased risk.
There was moderate‐certainty evidence that HPV vaccination reduces the incidence of CIN2+. Twelve cohort studies, three case‐control studies, three cross‐sectional studies and one RCT extension study reported a reduced risk of CIN2+ following HPV vaccination. Five pre‐post vaccine introduction studies reported a reduction in CIN2+ incidence following HPV introduction and one study reported an increased incidence.
There was moderate‐certainty evidence that HPV vaccination reduces the incidence of CIN2. Three cohort studies and one case‐control study reported a reduced risk of CIN2 following HPV vaccination. Two cross‐sectional studies reported no difference in risk of CIN2 between vaccinated and unvaccinated participants. Three pre‐post vaccine introduction studies reported a reduction in CIN2 incidence following HPV vaccine introduction.
There was moderate‐certainty evidence that HPV vaccination reduces the incidence of anogenital warts. Thirteen from 15 cohort studies reported a reduced risk of anogenital warts in vaccinated compared with unvaccinated participants. Twenty‐five pre‐post vaccine introduction studies reported a decrease in anogenital warts incidence following the introduction of HPV vaccine. Six studies reported no difference in anogenital warts incidence.
Specific adverse events
Across a range of study designs, there was moderate‐certainty evidence that HPV vaccination likely does not increase the risk of POTS, CFS/ME, paralysis, CRPS, premature ovarian failure, infertility or sexual activity. There was low‐certainty evidence that suggests HPV vaccination does not increase the risk of Guillain‐Barré syndrome.
Completeness
We have performed an extensive review of the published literature and engaged with clinicians and experts in this area to ensure comprehensive coverage of the literature in this field. The included studies reported data from 46 countries. Most of these are high‐income countries that have national HPV vaccination programmes that are often complemented with cervical screening programmes. There are fewer data on the effectiveness of HPV vaccination in lower‐income countries, where cervical cancer is more common and screening programmes are lacking.
The HPV vaccine was only licensed in 2006, so many of the population‐level studies that were included in this review had less than 10 years of follow‐up data. With a longer follow‐up, additional effectiveness questions, such as those around the number of doses required for protection, the effectiveness at different ages of vaccination or the effectiveness in males, can be answered with more confidence.
Applicability
The design of this review, with its objective to address population‐level impact, is directly related to the limitations of randomised controlled trial data assessing long‐term outcomes such as cancer (Bergman 2025). RCTs are unable to estimate the effects of vaccination strategies at a population level, where reducing the level of infection within a population can benefit both those vaccinated and those unvaccinated, if coverage is sufficient to induce a degree of herd immunity. However, population‐level studies often have less rigorous data collection procedures than RCTs for both the exposure and the outcome, as well as suffering from selection bias with limited opportunity to control for confounding. We refer readers to the companion review for a comprehensive analysis of RCT data on HPV vaccine efficacy (Bergman 2025).
The specific adverse events evaluated in this review were derived from a social media search (Appendix 2) to directly address the concerns of the public with regard to HPV vaccination. There is little evidence to suggest an association between HPV vaccines and the most mentioned adverse effects from social media.
Equality and diversity
Importantly, these data come largely from high‐income countries, whereas cervical cancer is predominately a disease of low‐ to middle‐income countries (WHO 2020). Improved vaccination and cervical screening coverage, especially in countries that lack resources for organised population‐level cervical cancer screening programmes, will be vital to achieve the WHO ambition for the elimination of cervical cancer in our lifetime (WHO 2023).
Quality of the evidence
The certainty of the evidence for different outcomes ranged from very low to moderate. In many cases, we downgraded the certainty due to limitations in study design. Overall risk of bias for the primary and secondary outcomes ranged from moderate risk to critical risk of bias. The observational and retrospective designs of most studies contributed to the high risk of bias. In retrospective studies, controlling for confounding between vaccinated and unvaccinated groups becomes challenging, especially when additional characteristics of the population are unknown or unrecorded. Many studies were carried out using routine healthcare administrative or insurance databases which, while large and rich in clinical data, are retrospective and can suffer from potential risk of measurement and outcome bias. We were unable to assess outcome reporting bias (failing to report on a planned outcome) for the included studies because most observational studies are not pre‐registered and often lack study protocols or statistical analysis plans.
For some outcomes, we downgraded the certainty of evidence by one level for inconsistency. This occurred when the effect estimates in the included studies were in different directions; that is, studies showed a combination of no effect, a possible harm and a possible benefit of HPV vaccination.
We did not downgrade any outcomes for indirectness. The outcomes were prespecified and only studies reporting one of the outcomes were included. The inclusion criteria of the review ensured that only the intervention and population of interest were considered.
Despite the large sample size of many included studies, we downgraded for imprecision if there were no or unclear numbers of outcome events.
Multiple data sets
We identified 347 published records for inclusion in this review, which were combined into 225 unique 'studies' or, more specifically, 'data sets'. We checked all records for overlapping sources of data (i.e. insurance databases or national registers) and dates to ensure participants and outcomes were only included once. This process limits the number of effectiveness estimates that can be derived from the same databases. However, this did involve selection of the most representative population and effect estimate that closely fit the outcomes of interest for this review.
We focussed on extracting effect estimates for different ages at vaccination, however this was often not reported or reported in inconsistent age groups. Further insight into the effectiveness of HPV vaccination at different ages of vaccination could be gained from re‐analysis of the original data sets in consistent age groups, as seen in other reviews (Drolet 2019).
We did not stratify analyses by type of vaccine because there were many more effectiveness estimates available for Gardasil than Cervarix or other HPV vaccines. Some studies did not specify the HPV vaccine in use or reported effectiveness estimates of the different vaccines combined.
Synthesis of evidence from different study types
By including a range of different observational study designs, we encountered challenges in combining data across studies and synthesising evidence for an outcome. The different designs provide insight into different aspects of HPV vaccine effectiveness.
Agreements and disagreements with other studies or reviews
The results of this review align closely with other systematic reviews of population‐level impact of the HPV vaccine (Drolet 2019; Ellingson 2023; Wang 2022).
In a large systematic review of the population‐based impact of HPV vaccination, Drolet 2019 reported that anogenital wart diagnoses decreased by 67% (RR 0.33, 95% CI 0.24 to 0.46) among girls aged 15 to 19 years, and 31% to 54% in older women. Our review had similar results when limiting the analysis to those receiving vaccination at or before 16 years (RR 0.30, 95% CI 0.20 to 0.43). Drolet 2019 also reported that CIN2+ decreased by 51% (RR 0.49, 95% CI 0.42 to 0.58) among screened girls aged 15 to 19 years and by 31% (RR 0.69, 95% CI 0.57 to 0.84) among women aged 20 to 24 years. Our results indicated a reduction of 62% (RR 0.38, 95% CI 0.31 to 0.45) in those receiving vaccination at or before 16 years.
In a review of the real‐world impact of the quadrivalent HPV vaccine, Wang 2022 reported reductions in infection, anogenital warts and cervical lesions across different regions of the world, similar to the results of the current review. Another review by Ellingson 2023 evaluated the effectiveness of HPV vaccine by age at vaccination. Results were similar to the sensitivity analysis in the current review, with the highest vaccine effectiveness in the youngest age group (9 to 14 years).
While the analytic approach between existing systematic reviews (Drolet 2019; Ellingson 2023; Wang 2022) and the current one differ, the overall results of the impact of HPV vaccination on genital HPV infection, anogenital warts and cervical lesions are similar.
The evaluation of specific adverse events that are commonly discussed on social media has been more limited than vaccine effectiveness outcomes. These events are rare and often not evaluated in clinical trials (Jørgensen 2020). We have attempted to prospectively identify all studies reporting on these specific adverse events and almost all studies did not report any association between HPV vaccination and these events.
Authors' conclusions
Implications for practice.
There are now long‐term outcome data from different countries and of different study designs that consistently demonstrate a probable reduction in the development of high‐grade cervical intraepithelial neoplasia (CIN) and cervical cancer in females vaccinated against human papillomavirus (HPV) in early adolescence. Data show that there is greater benefit to vaccinating younger adolescents prior to sexual debut, before most are exposed to high‐risk human papillomavirus (hrHPV) through sexual activity, whilst the benefit from vaccinating adults, untested for hrHPV, at a population level is minimal.
Data are now mature enough to see a beneficial effect of HPV vaccination, which probably reduces cervical cancer rates. Other HPV‐related cancers have a longer natural history, and it will take many more years, or even decades, to understand the impact of HPV vaccination on vulval, peri‐anal, and head and neck cancer diagnoses.
Data also show that HPV vaccination probably reduces the incidence of anogenital warts.
This will, most probably, result in a reduction in rates of high‐grade CIN (CIN2 or worse, CIN2+) and fewer HPV infections, and it will mean that cervical screening programmes will need to consider adapting, in order to remain cost‐effective. The introduction of primary HPV testing by some programmes has already enabled a change in screening intervals to five‐yearly (Morgan 2022; Public Health Scotland 2022), and these intervals could be even longer for those vaccinated in early adolescence (Rebolj 2022). This will have implications for service delivery at a laboratory level, especially in systems that employ HPV‐triage testing, since many fewer cytology samples will be screened, and in the delivery of colposcopy and cervical cancer care, including the training of healthcare professionals. Screening databases may also need to collate vaccination data to allow more personalised, adaptive screening.
Importantly, these data come largely from high‐income countries, whereas cervical cancer is predominately a disease of low‐ to middle‐income countries (WHO 2020). Improved vaccination coverage, especially in countries that lack resources for organised population‐level cervical cancer screening programmes, will be vital to achieve the World Health Organization (WHO) ambition for the elimination of cervical cancer in our lifetime (WHO 2023).
Implications for research.
The results of this review complement those of the parallel systematic review and network meta‐analysis of randomised controlled trial (RCT)‐level data for HPV vaccination (Bergman 2025). Taken together, these results demonstrate that RCTs alone are unable to answer important questions in research. These two reviews highlight the difficulty for RCTs alone to detect very rare harms and long‐term beneficial and adverse outcomes. RCTs, due to restrictions of time and funding, commonly have follow‐up time periods that are too short, and they are not powered to detect rarer outcomes in diseases with long natural histories or for effects on outcomes that happen later in life, for example cancers and pregnancy outcomes; these important outcomes are unlikely to be picked up in RCT studies of childhood vaccination.
Identification of valid short‐term surrogate markers for longer‐term important clinical endpoints is vital to avoid the significant harms of missing prevention opportunities over many years, or exposing people to unnecessary interventions, should they not work in practice. The decision to use HPV antibody levels, infection rates and development of CIN2+ as surrogate endpoints for cancer outcomes in these population‐level studies has proven legitimate (IARC 2014). If we had waited for evidence of effect on cervical cancer outcomes: 1) we would have had many years of lost opportunity to prevent death and disease; and 2) studies would have needed to be extremely large (and expensive) in order to demonstrate effects on rare outcomes in well‐screened study populations. Use of surrogate endpoints, therefore, has the potential to prevent avoidable harm and waste of health and research resources. However, these endpoints need to be based on the natural history of the disease and correlate well with the clinical outcomes we wish to measure, rather than be merely more convenient and cheaper.
Another limitation of the RCTs in HPV vaccination is that these studies were not performed in younger adolescents. This was due to the design of several studies, which required HPV testing from vaginal samples. Those that were performed concentrated on immunological outcomes, e.g. neutralising antibody titres. This therefore means that RCTs may underestimate the true effect of the intervention on the more ideal target: the prepubertal population that is likely to benefit the most.
One challenge for both this review and the parallel network meta‐analysis is the lack of standardisation of outcome measures and time points for measurement. This has made combining outcomes difficult, and often impossible, which limits the certainty of our conclusions. This is a shame and the development, and consistent implementation, of core outcome measures that are reported at agreed time points, is required with urgency in this area and many others.
Quality improvement (QI) methodology, including statistical process charts (SPC), may be better able to demonstrate trends and effects of interventions over time (Benneyan 2003). However, QI methodology on its own may not be able to exclude the possibility that change is due to other effects, unless used in parallel with more conventional cohort or case‐control studies. Combining these different types of studies to give a deeper understanding of the effects on long‐term health outcomes is an important challenge for methodologists.
History
Protocol first published: Issue 5, 2022
Acknowledgements
The review authors sincerely thank and acknowledge the editorial and information specialist staff of the Cochrane Gynaecological, Neuro‐oncology and Orphan Cancers Review Group, Clare Jess, Jo Platt, Gail Quinn and Tracey Harrison, for their advice and significant support in the preparation of this review. This review, and its partner review (Bergman 2025), are somewhat bitter‐sweet, as they represent the last of the reviews produced by the Gynaecological, Neuro‐oncology and Orphan Cancers Cochrane Review Group due to the ending of infrastructure funding for Cochrane review groups in the UK. This decision in no way reflects the high quality of the work done by the Gynaecological, Neuro‐oncology and Orphan Cancers Cochrane Review Group over many years. We thank them, not only for the work on this review, but for over a decade of friendship, support and dedication to the gynaecological oncology community and, most importantly, for helping to improve healthcare and decision‐making for people, especially women, with cancer.
The authors would like to thank Meghan Sebastianski, Jennifer Petkovic, Elise Cogo, Yanina Sguassero and Tie Yamato for their assistance with study screening and data extraction.
The review authors would like to thank the Cochrane Editorial Board and the Independent Advisory Group, led by Hilda Bastian, for their support and advice.
This project was supported by the National Institute for Health Research (NIHR), via Cochrane Programme Grant funding (Project NIHR133046) to the Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Group. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service (NHS) or the Department of Health.
The review authors would also like to thank Anna Noel‐Storr and the volunteer reviewers on the Cochrane Crowd platform for their assistance in screening abstracts for this review.
Editorial and peer‐reviewer contributions
The following people conducted the editorial process for this article:
Sign‐off Editor (final editorial decision): Robert Boyle, Cochrane Editorial Board, Imperial College London, UK.
Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Liz Bickerdike, Cochrane Central Editorial Service.
Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments and supported the editorial team): Leticia Rodrigues, Cochrane Central Editorial Service.
Copy Editor (copy editing and production): Jenny Bellorni, Cochrane Central Production Service.
Peer reviewers (provided comments and recommended an editorial decision): Ina Monsef, Cochrane Haematology, Institute of Public Health, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany (search); Nuala Livingstone, Cochrane Evidence Production and Methods Directorate (methods); Tiffany Duque, MPH, RDN, Cochrane Collaboration (consumer). Two additional reviewers provided clinical peer review but chose not to be publicly acknowledged.
Appendices
Appendix 1. Study design definitions
Population‐level studies
Pre‐ versus post‐vaccine introduction studies: a type of ecologic study that focuses on the comparison of groups, rather than individuals. Studies compare the frequency of an outcome between pre‐vaccination and post‐vaccination periods among the general population and should use the same population source and recruitment methods before and after vaccination. These types of studies are often considered to evaluate the 'impact' of vaccine introduction.
Interrupted time‐series study (ITS): a study that uses observations at multiple time points before and after an intervention (the ‘interruption’). The design attempts to detect whether the intervention, in this case HPV vaccine introduction, has had an effect significantly greater than any underlying trend over time (Reeves 2022).
Controlled before‐and‐after study (CBA): a study in which observations are made before and after the implementation of an intervention, both in a group that receives the intervention and in a control group that does not.
Individual‐level studies
Prospective cohort study/retrospective cohort study: an epidemiological study where groups of individuals are identified who vary in their exposure to an intervention or hazard and are followed to assess outcomes. Association between exposure and outcome are then estimated. Cohort studies are best performed prospectively (prospective cohort study) but can also be undertaken retrospectively (retrospective cohort study) if suitable data records are available. We will consider non‐randomised comparative studies, e.g. comparisons of a vaccinated group with an unvaccinated group, as a type of cohort study.
Cross‐sectional study: an epidemiological study that measures exposure and outcome at the same time. It reports the prevalence of exposure and outcome, and their associations, at a single point in time.
Case‐control study: an epidemiological study usually used to investigate the causes of disease. Study participants who have experienced an adverse outcome or disease are compared with participants who have not. Any differences in the presence or absence of hypothesised risk factors are noted.
Self‐controlled case series study (SCCS): uses individuals as their own controls. The ages at vaccination are regarded as fixed, and the age at the time of an adverse event is the random variable of interest within a predetermined observation period (Farrington 2004; Petersen 2016).
Appendix 2. Analysis of social media reporting of HPV vaccine adverse events
We sought to identify adverse events that were potentially related to HPV vaccination, which were commonly mentioned on social media.
Firstly, we screened all of the reviews on WebMD of HPV vaccines to identify mentions of adverse events. We coded each mention of a personal experience where possible to MedDRA preferred terms.
There were 276 adverse events mentioned and annotated. The most common adverse events were injection site pain, headaches and missed periods.
|
WebMD adverse event mentions (rank order of frequency) |
Adverse event |
| 1 | injection site pain |
| 2 | headache |
| 3 | missing periods |
| 4 | dizziness |
| 5 | fatigue |
| 6 | nausea |
| 7 | myalgia |
| 8 | fever |
| 9 | malaise |
| 10 | pain |
| 11 | syncope |
| 12 | abdominal pain |
| 13 | influenza‐like illness |
| 14 | alopecia |
| 15 | cramping |
| 16 | dyspnoea |
| 17 | rash |
| 18 | tremor |
| 19 | vomiting |
| 20 | anxiety |
| 21 | arthralgia |
| 22 | chest pain |
| 23 | cough |
| 24 | diarrhoea |
| 25 | infertility |
| 26 | syncope (recurrent) |
| 27 | tingling |
| 28 | aluminium toxicity |
| 29 | back pain |
| 30 | death |
| 31 | dehydration |
| 32 | hives |
| 33 | hypoaesthesia |
| 34 | insomnia |
| 35 | migraine |
| 36 | shoulder pain |
| 37 | swollen glands |
| 38 | seizure |
| 39 | auto‐immune disease |
We also investigated an analysis of 'Tweets' on X (formerly Twitter). Recent news events with the release of the results of a clinical trial and activity on Twitter related to the COVID‐19 vaccines meant that recent posts suffered from a lot of noise. Many posts mentioning adverse events were also doing so to promote an anti‐HPV vaccination stance rather than personal experience, with accounts dedicated to promoting HPV side effect information (@HPVSideEffects) and reference to the vaccine as ‘Human Paralysis inducing Vaccine’. Refusal of the vaccine was also stated to be related to parents not wanting to promote sexual activity in their children.
We were able to uncover 46 recent adverse event experience mentions.
|
Twitter adverse event mentions (rank order of frequency) |
Adverse event |
| 1 | death |
| 2 | auto‐immune disease |
| 3 | chronic fatigue syndrome |
| 4 | inability to walk |
| 5 | infertility |
| 6 | myalgic encephalomyelitis |
| 7 | paralysed |
| 8 | seizures/epilepsy |
| 9 | tremors |
| 10 | aluminium toxicity |
| 11 | anxiety |
| 12 | chronic kidney disease |
| 13 | encephalitis |
| 14 | epilepsy |
| 15 | Epstein Barr |
| 16 | functional neurologic disorder |
| 17 | Hashimoto's disease |
| 18 | heart problem |
| 19 | missing periods |
| 20 | myocarditis |
| 21 | nervous breakdown |
| 22 | pain |
| 23 | postural orthostatic tachycardia syndrome |
| 24 | stuttering |
| 25 | syncope |
| 26 | systemic lupus erythematosus |
| 27 | weakness |
| 28 | amyotrophic lateral sclerosis |
Appendix 3. MEDLINE search strategy
1. exp Papillomavirus Vaccines/ 2. gardasil*.mp. 3. (cervarix* or cecolin*).mp. 4. ((human papilloma virus* or human papiloma virus*) adj (vaccin* or immuni*)).tw. 5. ((human papillomavirus* or human papilomavirus*) adj (vaccin* or immuni*)).tw. 6. (HPV* adj3 (vaccin* or immuni*)).tw. 7. 1 or 2 or 3 or 4 or 5 or 6 8. ae.fs. 9. safe*.ti,ab. 10. de.fs. 11. adverse.ti,ab. 12. co.fs. 13. side effect*.ti,ab. 14. complication*.ti,ab. 15. ci.fs. 16. tolerated.ti,ab. 17. tolerance.ti,ab. 18. harm*.ti,ab. 19. toxicity.ti,ab. 20. risk.ti. 21. Pregnancy complications/dt 22. Clinical trial phase IV.pt. 23. Drug hypersensitivity/ 24. Tolerability.ti,ab. 25. to.fs. 26. toxicology/ 27. Drug induced.ti,ab. 28. Negative effects.ti,ab. 29. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 30. exp cohort studies/ or exp epidemiologic studies/ or exp clinical trial/ or exp evaluation studies as topic/ or exp statistics as topic/ 31. (control and (group* or study)).mp. 32. (time and factors).mp. 33. Program.mp. 34. survey*.mp. 35. ci.mp. 36. cohort.mp. 37. (comparative stud* or prospective* or retrospective* or longitudinal*).mp. 38. evaluation studies.mp. 39. 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 40. (animals/ not humans/) or comment/ or editorial/ or exp review/ or meta analysis/ or consensus/ or exp guideline/ 41. case report.mp. 42. 40 or 41 43. 39 not 42 44. 7 and 29 45. 43 and 44
Appendix 4. Embase search strategy
1. exp Wart virus vaccine/
2. gardasil*.mp.
3. cervarix*.mp.
4. ((human papilloma virus* or human papiloma virus*) adj (vaccin* or immuni*)).tw.
5. ((human papillomavirus* or human papilomavirus*) adj (vaccin* or immuni*)).tw.
6. (HPV* adj3 (vaccin* or immuni*)).tw.
7. 1 or 2 or 3 or 4 or 5 or 6
8. exp Papillomavirus Infection/
9. exp Papillomaviridae/
10. (HPV* or papilloma*).ti,ab.
11. uterine cervix carcinoma in situ/
12. Uterine Cervical Dysplasia/
13. (CIN* or adenocarcinoma in situ or AIS).ti,ab.
14. (cervi* adj5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*)).ti,ab.
15. ($genit* adj5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*)).ti,ab.
16. (vagina* adj5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*)).ti,ab.
17. (vulv* adj5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*)).ti,ab.
18. (anal* adj5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*)).ti,ab.
19. ((head or neck) adj5 (neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or disease* or maligna*)).ti,ab.
20. (penile* adj5 (wart* or infection* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*)).ti,ab.
21. Uterine Cervix Tumor/
22. exp Condylomata Acuminata/
23. vulva tumor/ or vagina tumor/ or anus tumor/ or anus disease/
24. "Head and Neck Neoplasms"/
25. penis tumor/ or penis disease/
26. Postural Orthostatic Tachycardia Syndrome/
27. (postural tachycardia syndrome* or postural orthostatic tachycardia syndrome* or POTS).mp.
28. Chronic Fatigue Syndrome/
29. chronic fatigue*.mp.
30. (myalgic encephalomyelitis or ME or chronic fatigue* or CFS).mp.
31. Paralysis/
32. paralys*.mp.
33. Complex Regional Pain Syndrome/
34. (complex regional pain syndrome or CRPS).mp.
35. premature ovarian failure/
36. ((premature ovar* or primary ovar*) adj2 (fail* or insufficien*)).mp.
37. Guillain‐Barre Syndrome/
38. (Guillain Barr* syndrome or GBS).mp.
39. Infertility/
40. infertil*.mp.
41. Sexual Behavior/
42. (earl* adj3 (sex* activity or sex* behaviour)).mp.
43. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42
44. ae.fs.
45. Adverse.ti,ab,kw,ox.
46. Safe*.ti,ab,kw.
47. Po.fs.
48. Co.fs.
49. exp adverse drug reaction/
50. Complication*.ti,ab,kw.
51. Drug safety/
52. To.fs.
53. Side effect*.ti,ab.
54. Risk.ti.
55. Tolerance.ti,ab.
56. Tolerated.ti,ab.
57. Harm.ti,ab.
58. Side reaction*.ti,ab.
59. drug withdrawal/
60. health risks.ti,ab.
61. potential risks.ti,ab.
62. toxic effects.ti,ab.
63. toxicity.ti,ab.
64. toxicities.ti,ab.
65. 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64
66. 43 or 65
67. 7 and 66
Appendix 5. CENTRAL search strategy
#1 MeSH descriptor: [Papillomavirus Vaccines] explode all trees
#2 gardasil*
#3 cervarix*
#4 ((human papilloma virus* or human papiloma virus*) near (vaccin* or immuni*))
#5 ((human papillomavirus* or human papilomavirus*) near (vaccin* or immuni*))
#6 (HPV* near/3 (vaccin* or immuni*))
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 MeSH descriptor: [Papillomavirus Infections] explode all trees
#9 MeSH descriptor: [Papillomaviridae] explode all trees
#10 (HPV* or papilloma*)
#11 MeSH descriptor: [Cervical Intraepithelial Neoplasia] this term only
#12 MeSH descriptor: [Uterine Cervical Dysplasia] this term only
#13 (CIN* or adenocarcinoma in situ or AIS)
#14 (cervi* near/5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*))
#15 ($genit* near/5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*))
#16 (vagina* near/5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*))
#17 (vulv* near/5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*))
#18 (anal* near/5 (wart* or infection* or condyloma* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*))
#19 ((head or neck) near/5 (neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or disease* or maligna*))
#20 (penile* near/5 (wart* or infection* or neoplas* or dysplas* or lesion* or cancer* or precancer* or "pre‐cancer*" or "pre‐invasive" or preinvasive or "intra‐epithel*" or intraepithelial* or disease* or maligna*))
#21 MeSH descriptor: [Uterine Cervical Neoplasms] this term only
#22 MeSH descriptor: [Condylomata Acuminata] explode all trees
#23 MeSH descriptor: [Vulvar Neoplasms] this term only
#24 MeSH descriptor: [Vaginal Neoplasms] this term only
#25 MeSH descriptor: [Anus Neoplasms] explode all trees
#26 MeSH descriptor: [Anus Diseases] this term only
#27 MeSH descriptor: [Head and Neck Neoplasms] this term only
#28 MeSH descriptor: [Penile Neoplasms] this term only
#29 MeSH descriptor: [Penile Diseases] this term only
#30 MeSH descriptor: [Postural Orthostatic Tachycardia Syndrome] this term only
#31 (postural tachycardia syndrome* or postural orthostatic tachycardia syndrome* or POTS)
#32 MeSH descriptor: [Fatigue Syndrome, Chronic] this term only
#33 chronic fatigue*
#34 (myalgic encephalomyelitis or ME or chronic fatigue* or CFS)
#35 MeSH descriptor: [Paralysis] this term only
#36 paralys*
#37 MeSH descriptor: [Complex Regional Pain Syndromes] this term only
#38 complex regional pain syndrome or CRPS
#39 MeSH descriptor: [Primary Ovarian Insufficiency] this term only
#40 ((premature ovar* or primary ovar*) near/2 (fail* or insufficien*))
#41 MeSH descriptor: [Guillain‐Barre Syndrome] this term only
#42 Guillain Barr* syndrome or GBS
#43 MeSH descriptor: [Infertility] this term only
#44 infertil*
#45 MeSH descriptor: [Sexual Behavior] this term only
#46 (earl* near/3 (sex* activity or sex* behaviour))
#47 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46
#48 #7 and #47
Data and analyses
Comparison 1. Primary clinical outcomes.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Invasive cervical cancer (cohort studies; long‐term) | 5 | Risk Ratio (IV, Random, 95% CI) | 0.37 [0.25, 0.56] | |
| 1.2 Invasive cervical cancer (cohort studies; long‐term; ≤ 16 years at vaccination) | 3 | Risk Ratio (IV, Random, 95% CI) | 0.20 [0.09, 0.44] | |
| 1.3 Invasive cervical cancer (RCT extension studies; medium/long‐term) | 3 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.3.1 Medium‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.15 [0.01, 2.36] | |
| 1.3.2 Long‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.15 [0.02, 1.17] | |
| 1.4 CIN3+ (cohort studies; medium/long‐term) | 8 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.4.1 Medium‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.43 [0.35, 0.53] | |
| 1.4.2 Long‐term | 7 | Risk Ratio (IV, Random, 95% CI) | 0.39 [0.32, 0.48] | |
| 1.5 CIN3+ (cohort studies; medium/long‐term; ≤ 16 years at vaccination) | 3 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.5.1 Medium‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.43 [0.35, 0.53] | |
| 1.5.2 Long‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.26 [0.12, 0.56] | |
| 1.6 CIN3 (cohort studies; long‐term) | 1 | Risk Ratio (IV, Random, 95% CI) | 0.17 [0.06, 0.45] | |
| 1.7 CIN3 (cohort studies; long‐term; ≤ 16 years at vaccination) | 1 | Risk Ratio (IV, Random, 95% CI) | 0.09 [0.01, 0.70] | |
| 1.8 CIN2+ (cohort studies; medium/long‐term) | 9 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.8.1 Medium‐term | 3 | Risk Ratio (IV, Random, 95% CI) | 0.62 [0.45, 0.85] | |
| 1.8.2 Long‐term | 6 | Risk Ratio (IV, Random, 95% CI) | 0.51 [0.41, 0.64] | |
| 1.9 CIN2+ (cohort studies; medium/long‐term; ≤ 16 years at vaccination) | 7 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.9.1 Medium‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.59 [0.54, 0.65] | |
| 1.9.2 Long‐term | 5 | Risk Ratio (IV, Random, 95% CI) | 0.38 [0.31, 0.45] | |
| 1.10 CIN2+ (cross‐sectional studies; medium/long‐term) | 4 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.10.1 Medium‐term | 3 | Risk Ratio (IV, Random, 95% CI) | 0.62 [0.28, 1.34] | |
| 1.10.2 Long‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.46 [0.21, 1.00] |
Comparison 2. Specific adverse events.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2.1 Postural orthostatic tachycardia syndrome (cohort studies) | 2 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 2.1.1 Short‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.87 [0.34, 2.22] | |
| 2.1.2 Medium‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.46, 2.12] | |
| 2.2 Chronic fatigue syndrome/myalgic encephalomyelitis (cohort studies; short/medium‐term) | 4 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 2.2.1 Short‐term | 3 | Risk Ratio (IV, Random, 95% CI) | 0.40 [0.22, 0.75] | |
| 2.2.2 Medium‐term | 3 | Risk Ratio (IV, Random, 95% CI) | 0.96 [0.67, 1.39] | |
| 2.3 Chronic fatigue syndrome/myalgic encephalomyelitis (self‐controlled case series; medium‐term) | 3 | Risk Ratio (IV, Random, 95% CI) | 0.74 [0.40, 1.39] | |
| 2.4 Paralysis (cohort studies; short/medium/long‐term) | 5 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 2.4.1 Short‐term | 4 | Risk Ratio (IV, Random, 95% CI) | 0.54 [0.39, 0.74] | |
| 2.4.2 Medium‐term | 3 | Risk Ratio (IV, Random, 95% CI) | 0.61 [0.39, 0.96] | |
| 2.4.3 Long‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.62 [0.36, 1.07] | |
| 2.5 Complex regional pain syndrome (cohort studies; immediate/short/medium/long‐term) | 3 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 2.5.1 Immediate‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.90 [0.46, 1.75] | |
| 2.5.2 Short‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.95 [0.46, 1.96] | |
| 2.5.3 Medium‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.43 [0.18, 1.03] | |
| 2.5.4 Long‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.76 [0.62, 0.94] | |
| 2.6 Guillain‐Barré syndrome (cohort studies; short/medium/long‐term) | 6 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 2.6.1 Short‐term | 4 | Risk Ratio (IV, Random, 95% CI) | 0.78 [0.10, 6.03] | |
| 2.6.2 Medium‐term | 4 | Risk Ratio (IV, Random, 95% CI) | 1.56 [0.40, 5.99] | |
| 2.6.3 Long‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.89 [0.36, 2.20] | |
| 2.7 Guillain‐Barré syndrome (self‐controlled case series) | 3 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 2.7.1 Immediate‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 1.98 [0.55, 7.12] | |
| 2.7.2 Short‐term | 3 | Risk Ratio (IV, Random, 95% CI) | 1.53 [0.78, 2.98] | |
| 2.8 Premature ovarian failure (cohort studies; short/medium/long‐term) | 3 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 2.8.1 Short‐term | 2 | Risk Ratio (IV, Random, 95% CI) | 0.21 [0.03, 1.28] | |
| 2.8.2 Medium‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.91 [0.55, 1.51] | |
| 2.8.3 Long‐term | 1 | Risk Ratio (IV, Random, 95% CI) | 0.96 [0.55, 1.68] |
Comparison 3. Secondary clinical outcomes.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 3.1 Cervical screening attendance (cohort studies; long‐term) | 2 | Risk Ratio (IV, Random, 95% CI) | 1.60 [1.57, 1.62] | |
| 3.2 Anogenital warts (cohort studies; medium/long‐term) | 15 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 3.2.1 Medium‐term | 4 | Risk Ratio (IV, Random, 95% CI) | 0.53 [0.37, 0.77] | |
| 3.2.2 Long‐term | 13 | Risk Ratio (IV, Random, 95% CI) | 0.47 [0.36, 0.61] | |
| 3.3 Anogenital warts (cohort studies; medium/long‐term; ≤ 16 years at vaccination) | 8 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 3.3.1 Medium‐term | 3 | Risk Ratio (IV, Random, 95% CI) | 0.60 [0.30, 1.21] | |
| 3.3.2 Long‐term | 6 | Risk Ratio (IV, Random, 95% CI) | 0.30 [0.20, 0.43] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Abel 2021‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; 2009‐2016 V: self‐report O: oral rinse samples |
|
| Participants | N = 5798 females 18 to 36 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, repeated over 8 years |
|
| Notes | Source of funding: public/non‐profit: Denise Cobb Hale; The Fisher Family Fund Conflicts of interest: some authors received funding from the vaccine developer |
|
Ahrlund‐Richter 2019‐SWE.
| Study characteristics | ||
| Methods | Cohort study Sweden; 2008‐2018 V: youth clinic O: youth clinic |
|
| Participants | N = 1274 females 15 to 23 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: not reported |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Ferring Pharmaceuticals, the Swedish Foundation for Strategic Research (SSF), ÅkeWibergs Foundation, Jeanssons Foundation, The Stockholm Cancer Foundation, The Swedish Cancer Foundation, The Swedish Cancer and Allergy Foundation, Fredrik and Ingrid Thurings Foundation, The Foundations Längmanska Kulturfonden, Lars Hiertas Minne, Clas Groschinskys Minnesfond, Föreningen för Klinisk Mikrobiologi, Svenska Läkaresällskapet, The Stockholm City Council, Karolinska Institutet, and Grigore T Conflicts of interest: no |
|
Ali 2013‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; 2000‐2011 V: no individual vaccination status O: Medicare, the universal health insurance scheme of Australia (insurance database) |
|
| Participants | N = 6950 GW cases/national population females and males 15 to 44 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 12 years |
|
| Notes | Source of funding: private/industry: CSL Biotherapies Conflicts of interest: authors include stockholders of the vaccine developer |
|
Andrews 2017‐GBR.
| Study characteristics | ||
| Methods | Self‐controlled case series United Kingdom (UK); September 2007‐March 2016 V: GP records/community child health information system (CHIS) (national database) O: Hospital Episode Statistics (HES) database (national database) |
|
| Participants | N = 100 females 11 to 19 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Guillain‐Barré syndrome (GBS) Follow‐up: 10 years |
|
| Notes | Source of funding: public/non‐profit: Public Health England Conflicts of interest: no |
|
Arnheim‐Dahlström 2013‐DNK/SWE.
| Study characteristics | ||
| Methods | Cohort study Denmark, Sweden: October 2006 to December 2010 V: Denmark: the childhood vaccination database at Statens Serum Institut + national prescription register; Sweden: Svevac (national HPV vaccination register, established in 2006 and held by the Swedish Institute for Communicable Disease) and the drug prescription register held by the National Board of Health and Welfare (national databases) O: national patient registers in both countries using ICD‐10 codes (national databases) |
|
| Participants | N = 997585 females 12 to 17 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Paralysis; Guillain‐Barré syndrome (GBS) Follow‐up: 6 months |
|
| Notes | Source of funding:public/non‐profit: the Swedish Foundation for Strategic Research and the Danish Medical Research Council Conflicts of interest: some authors received funding from the vaccine developer |
|
Ba 2021‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; January 2006 to December 2016 V: claims of HPV vaccine using current procedural terminology (CPT) codes O: ICD‐9 and ICD‐10 codes for cervical screening |
|
| Participants | N = 954910 females 21 to 26 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent), Gardasil 9 (Merck nonavalent) | |
| Outcomes | Participation rates in screening Follow‐up: at least 30 days after the index date |
|
| Notes | Funding: no specific funding Conflicts of interest: no |
|
Baandrup 2021‐DNK.
| Study characteristics | ||
| Methods | Cohort study Denmark; 2006‐2016 V: Danish National Health Service Register; Danish National Prescription Registry (national database) O: Danish National Prescription Registry; Danish National Patient Register (national database) |
|
| Participants | N = 1,076,945 females 12 to 31 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: up to 10 years |
|
| Notes | Source of funding: public/non‐profit: the Mermaid project Conflicts of interest: some authors received funding from the vaccine developer |
|
Baandrup 2024‐DNK.
| Study characteristics | ||
| Methods | Retrospective cohort study Denmark; October 2006‐December 2021 V: National Health Service register and National Prescription registry (national database) O: Danish pathology registry (national database) |
|
| Participants | N = 926881 females 17 to 32 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent), Gardasil 9 (Merck nonavalent) | |
| Outcomes | Anal intraepithelial neoplasia (AIN) Follow‐up: 15 years |
|
| Notes | Funding: public/non‐profit: the Mermaid project (MERMAID II) Conflict of interest: none |
|
Badre‐Esfahani 2019‐DNK.
| Study characteristics | ||
| Methods | Cohort study Denmark; October 2008‐December 2017 V: Danish National Health Service Register O: Danish Pathology Register (data on participation in the Danish National Cervical Cancer Screening Programme) |
|
| Participants | N = 24828 females 22 to 24 years |
|
| Interventions | Not reported | |
| Outcomes | Participation rates in screening Follow‐up: 18 months (after 22.5 years of age) |
|
| Notes | Source of funding: public/non‐profit: Family Hede Nielsen’s Foundation and Helsefonden Conflicts of interest: an author received a speaker's fee from the vaccine developers |
|
Baldur‐Felskov 2014‐DNK.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Denmark; January 2000‐March 2013 V: individual vaccination status not used ‐ pre‐/post‐introduction populations O: nationwide Pathology Data Bank (national database) |
|
| Participants | N > 2,500,000 females > 12 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+; participation rates in screening Follow‐up: 12 years |
|
| Notes | Source of funding:public/non‐profit: the Mermaid project (MERMAID II) Conflicts of interest: some authors received funding from the vaccine developer |
|
Baldur‐Felskov 2015‐DNK.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Denmark; 1997‐2019 V: not reported O: Danish Cancer Registry (national database) |
|
| Participants | N = 5927 females 12 to 99 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; adenocarcinoma in situ; CIN3 Follow‐up: not reported |
|
| Notes | Source of funding:public/non‐profit: the Mermaid project (MERMAID II) Conflicts of interest: some authors received funding from the vaccine developer |
|
Balgovind 2024‐AUS.
| Study characteristics | ||
| Methods | Cross‐sectional study Australia; January 2015‐November 2018 V: National HPV Vaccination Program Register; self‐report O: HPV DNA detection and genotyping |
|
| Participants | N = 1625 males 18 to 35 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, up to 8 years since vaccination |
|
| Notes | Source of funding: public/non‐profit: Commonwealth Department of Health HPV Surveillance Fund Conflicts of interest: some authors received funding from the vaccine developer |
|
Baril 2015‐GBR.
| Study characteristics | ||
| Methods | Cohort study United Kingdom (UK); September 2008‐June 2011 V: Clinical Practice Research Datalink (national database) O: Clinical Practice Research Datalink (national database) |
|
| Participants | N = 962 females 14 to 23 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Birth outcomes Follow‐up 3 years |
|
| Notes | Source of funding:private/industry: GlaxoSmithKline Biologicals SA Conflicts of interest: authors include employees of the vaccine developer |
|
Batmunkh 2019‐MNG.
| Study characteristics | ||
| Methods | Cohort study Mongolia; August 2017‐January 2018 V: participants vaccinated in the preceding original trial O: self‐administered vaginal swabs were analysed |
|
| Participants | 1587 trial participants, community controls, females 18 to 23 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Australian Department of Foreign Affairs and Trade Direct Aid Program; Murdoch Children's Research Institute and the World Health Organization, Mongolia office; Bill & Melinda Gates Foundation Conflicts of interest: none |
|
Batmunkh 2020‐MNG.
| Study characteristics | ||
| Methods | Cohort study Mongolia; September 2018‐February 2019 V: immunisation records at the National Center for Communicable Diseases, Ulaanbaatar O: self‐administered vaginal swab for HPV detection and to complete a short questionnaire |
|
| Participants | N = 475 females 16 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 6 years |
|
| Notes | Source of funding: public/non‐profit: Bill & Melinda Gates Foundation Conflicts of interest: no |
|
Bauer 2012‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; 2007‐2010 V: no individual vaccination status O: clinical encounter claims data from the California Family Planning Access Care and Treatment (Family PACT) program (insurance database) |
|
| Participants | N = n/a (different total by year) females and males < 21 to ≥ 31 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: the Centers for Disease Control and Prevention and the California Department of Public Health, Office of Family Planning Conflicts of interest: no information |
|
Baussano 2020‐BTN.
| Study characteristics | ||
| Methods | Cohort study Bhutan; 2011‐2018 V: self‐report O: cervical cell collection, DNA extraction, and HPV testing and genotyping |
|
| Participants | N = 3040 females 17 to 29 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, follow‐up potentially to 7 years after vaccination |
|
| Notes | Source of funding: public/non‐profit: Bill & Melinda Gates Foundation Conflicts of interest: unclear |
|
Baussano 2021‐RWA/BTN.
| Study characteristics | ||
| Methods | Cohort study Bhutan and Rwanda; 2013‐2017 V: self‐report O: urine collection and DNA extraction |
|
| Participants | N = 3881 females 17 to 22 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Bill and Melinda Gates Foundation Conflicts of interest: some authors hold shares in companies with related interests |
|
Bednarczyk 2012‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; July 2006‐December 2010 V: Kaiser Permanente Georgia clinical (routine administrative database, insurance) O: Kaiser Permanente Georgia clinical (routine administrative database, insurance) |
|
| Participants | N = 1398 females 14 to 16 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Sexual activity (incidence of sexually transmitted infections) Follow‐up: up to 3 years |
|
| Notes | Funding: no specific funding Conflicts of interest: some authors received funding from the vaccine developer |
|
Benard 2017‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; January 2007‐December 2020 V: no individual vaccination status reported or used ‐ pre‐/post‐vaccine analysis O: the New Mexico HPV Pap Registry (NMHPVPR) (national database) |
|
| Participants | N = 219797 females attending cervical screening 15 to 29 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3; CIN2 Follow‐up: cross‐sectional, repeated over 14 years |
|
| Notes | Source of funding: public/non‐profit: National Institute of Allergy and Infectious Diseases Conflicts of interest: some authors received funding from the vaccine developer |
|
Berenson 2021‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; 2011‐2016 V: self‐report O: oral sample |
|
| Participants | N = 9437 females and males 18 to 59 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Cancer Prevention and Research Institute of Texas Conflicts of interest: no |
|
Bertoli 2020‐DNK.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Denmark; January 1978‐December 2017 V: no individual vaccination status reported or used ‐ pre‐/post‐vaccine analysis O: The Danish Pathology Register and the Danish Cancer Registry (national database) |
|
| Participants | N = not reported, females All ages |
|
| Interventions | Not reported | |
| Outcomes | Vaginal cancer Follow‐up: 39 years |
|
| Notes | Source of funding: not reported Conflicts of interest: some authors received funding from the vaccine developer |
|
Bobadilla 2024‐PAR.
| Study characteristics | ||
| Methods | Cross‐sectional study Paraguay; May 2020‐September 2023 V: self‐report O: Central Laboratory of Public Health |
|
| Participants | N = 254 females 18 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Funding: National Council of Science and Technology Conflicts of interest: none |
|
Bogaards 2019‐NLD.
| Study characteristics | ||
| Methods | Cross‐sectional study Netherlands; 2011‐2017 V: self‐report O: vaginal swab |
|
| Participants | N = 2104 females 16 to 24 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, up to 8 years after vaccination |
|
| Notes | Source of funding: public/non‐profit: Dutch Ministry of Health, Welfare and Sport; Strategic Programme from the National Institute for Public Health and the Environment Conflicts of interest: no |
|
Boone 2016‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; July 2006‐July 2013 V: vaccination status was ascertained from patient logs maintained for vaccine accountability, billing records and EMR searches for quadrivalent HPV vaccine, HPV4 or Gardasil O: electronic medical records |
|
| Participants | N = 2246 females 14 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Participation rates in screening Follow‐up: 7 years |
|
| Notes | Funding: no specific funding Conflicts of interest: none |
|
Brotherton 2019‐AUS.
| Study characteristics | ||
| Methods | Cohort study; retrospective cohort study/database linkage Australia; 1 January 2000–31 December 2014 V: National HPV Vaccination Program Register (NHVPR) (national database) O: National Cervical Screening Program (national database) |
|
| Participants | N = 250,648 females 15 to 22 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN2+ Follow‐up: median follow‐up time of 1.7 years (IQR 0.8 to 2.5 years) |
|
| Notes | Source of funding: public/non‐profit: Australian Department of Health; National Health and Medical Research Council; Centre for Research Excellence in Cervical Cancer Control Conflicts of interest: none |
|
Bukowinski 2020‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; 2007‐2014 V: Defense Manpower Data Center (national database) O: inpatient/outpatient records (study‐level targeted ascertainment) |
|
| Participants | N = 906,000 females 17 to 28 years |
|
| Interventions | Gardasil | |
| Outcomes | Birth outcomes Follow‐up: not reported |
|
| Notes | Source of funding:public/non‐profit: Defense Health Agency Immunization Healthcare Division and US Navy Bureau of Medicine and Surgery Conflicts of interest: none |
|
Cameron 2016‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐ vaccine introduction United Kingdom (UK); 2004‐2014 V: no individual vaccine status reported O: hospital discharge data, generated by Scottish National Health Service (national database) |
|
| Participants | N = not reported, females and males 12 to 18 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME); Guillain‐Barré syndrome (GBS) Follow‐up: not reported |
|
| Notes | Funding: no specific funding Conflicts of interest: none |
|
Canvin 2017‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom (UK); 2009‐2014 V: no individual vaccination status (coverage estimates from published reports) O: GUM Clinic Activity Dataset (GUMCADv2) submitted by GUM and integrated GUM/sexual and reproductive health clinics (national database) |
|
| Participants | N = not reported, females and males (attending sexual health clinic) 15 to 24 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: repeated cross‐sectional 2009‐2014 |
|
| Notes | Source of funding: public/non‐profit: Public Health England Conflicts of interest: no |
|
Carnalla 2021‐MEX.
| Study characteristics | ||
| Methods | Cohort study Mexico 2017‐2019 V: participants vaccinated in the preceding original trial O: lab test HPV DNA in urine was determined with the commercial kit BD OnclarityTM HPV Assay |
|
| Participants | N = 232 females 17 to 19 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Funding: no specific funding Conflicts of interest: none |
|
Carozzi 2018‐ITA.
| Study characteristics | ||
| Methods | Cohort study Italy; May 2012 to February 2014 V: official computerised HPV vaccine registry of the LHU of Matera O: at the enrolment visit, two cervical samples (one each for Pap and HPV testing) were obtained, and participants completed self‐administered sociodemographic and behavioural questionnaires |
|
| Participants | N = 2804 females 24 to 50 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: not reported |
|
| Notes | Source of funding: private/industry: Sanofi‐Pasteur Conflicts of interest: authors include employees of the vaccine developer |
|
Castle 2019‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; December 2006‐May 2017 V: Kaiser Permanente Northern California (insurance database) O: Kaiser Permanente Northern California (insurance database) |
|
| Participants | N = 75,649 females attending cervical screening 21 to 24 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN2+ Follow‐up: 3 years |
|
| Notes | Source of funding: not reported Conflicts of interest: some authors received funding from the vaccine developer |
|
Chambers 2022‐CAN.
| Study characteristics | ||
| Methods | Cross‐sectional study Canada; February 2017‐August 2019 V: self‐report O: anal specimens were self‐collected at study sites using moistened Dacron swabs |
|
| Participants | N = 645 males 16 to 30 years |
|
| Interventions | Gardasil (Merck quadrivalent), Gardasil 9 (Merck nonavalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Canadian Institutes of Health Research, the CIHR Canadian HIV/AIDS Trials Network, the Canadian Association for HIV/AIDS Research, the Ontario HIV Treatment Network, the Public Health Agency of Canada, Ryerson University, the Canadian Immunization Research Network. The HIV/AIDS network of Fonds de Recherche du Québec – Santé supported quality assurance and control of human papillomavirus testing. Conflicts of interest: some authors received funding from the vaccine developer |
|
Cho 2024‐KOR.
| Study characteristics | ||
| Methods | Retrospective cohort study/database linkage Korea; July 2011‐December 2021 V: Immunization Registry Integration System O: National Health Information Database |
|
| Participants | N = 332,062 females 12 to 13 years |
|
| Interventions | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Anogenital warts | |
| Notes | Funding source: none Conflicts of interest: none |
|
Chow 2017‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; July 2004‐June 2015 V: no individual vaccination status O: stored chlamydia‐positive, urine and urethral swab specimens |
|
| Participants | N = 1466 males ≤ 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 11 years |
|
| Notes | Source of funding: public/non‐profit: The Australian National Health and Medical Research Council Program Conflicts of interest: authors include stockholders of the vaccine developer |
|
Chow 2019‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐ vaccine introduction Australia; 2014‐2017 V: self‐reported vaccine doses were confirmed with doses reported to the National HPV Vaccination Program Register O: males provided a self‐collected penile swab for 37 HPV genotypes using Roche Linear Array and completed a questionnaire (study‐level targeted ascertainment) |
|
| Participants | N = 298 males (attending sexual health clinic) 17 to 19 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts; prevalent HPV infection Follow‐up: cross‐sectional, 2 years after possible vaccination |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Merck & Co.; Australian Government Department of Health Conflicts of interest: authors include stockholders of the vaccine developer |
|
Chow 2021a‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; October 2010‐December 2018 V: National HPV Vaccination Program Register (before October 2018) or the Australian Immunisation Register (after October 2018) O: participants provided three specimens for HPV genotyping: an anal swab, a penile swab and an oral rinse |
|
| Participants | N = 400 males 16 to 20 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional (repeated) |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Merck; Australian Government Department of Health Conflicts of interest: authors include stockholders of the vaccine developer |
|
Chow 2021b‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; January 2004‐December 2018 V: no individual vaccination status O: clinical diagnosis of genital warts for all new patients who attended the GWSN sexual health clinics (study‐level targeted ascertainment) |
|
| Participants | N = 237,379 females and males (attending sexual health clinic) ≥ 15 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional, repeated over 15 years |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Seqirus Australia; Australian Government Department of Health Conflicts of interest: some authors received funding from the vaccine developer |
|
Clark 2021‐CAN.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Canada; January 2003‐December 2018 V: not reported O: Cytobase, database of patient medical records of Pap tests performed in Ontario |
|
| Participants | N = 221,039 females 18 to 23 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Treatment rates for CIN and other HPV‐related disease Follow‐up: 5 years |
|
| Notes | Funding: no specific funding Conflicts of interest: none |
|
Closson 2020‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; 2013‐2016 V: self‐report (National Health and Nutrition Examination Survey) O: self‐collected urine and cervicovaginal samples |
|
| Participants | N = 1050 females 18 to 35 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Funding: no specific funding Conflicts of interest: some authors received funding from the vaccine developer |
|
Cocchio 2017‐ITA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Italy; 2004‐2015 V: no individual vaccination status O: hospital discharge records (hospital database) |
|
| Participants | N = 6076 females and males 12 to 48+ years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional (repeated) |
|
| Notes | Source of funding: public/non‐profit: university grant Conflicts of interest: no |
|
Combita 2021‐COL.
| Study characteristics | ||
| Methods | Cross‐sectional study Colombia; May 2014‐February 2015 and January 2016‐December 2018 V: self‐administered questionnaire O: each woman underwent a gynaecologic examination, and two cervical samples (one each for Pap and HPV testing) were obtained |
|
| Participants | N = 3273 females 18 to 25 years |
|
| Interventions | Cross‐sectional (repeated) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Colombian Health and Social Protection Ministry Conflicts of interest: none |
|
Crowe 2014‐AUS.
| Study characteristics | ||
| Methods | Case‐control study Australia; April 2007 and March 2011 V: Queensland Health Vaccination Information Vaccination Administration System O: Queensland Health Pap Smear Register |
|
| Participants | N = 108,353 females Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+ Follow‐up: median follow‐up time from study start date to index date 808 days (interquartile range 456 to 1131 days) |
|
| Notes | Funding: no specific funding Conflicts of interest: not reported |
|
Cruickshank 2017‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom (UK); 2008‐2014 V: individual vaccination status not used. Pre‐/post‐vaccine analysis. O: colposcopy results from National Colposcopy Clinical Information and Audit System (NCCIAS) (national database) |
|
| Participants | N = 7013 females attending colposcopy 20 to 21 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+; treatment rates for CIN and other HPV‐related disease Follow‐up: 7 repeated cross‐sectional surveys |
|
| Notes | Source of funding:public/non‐profit: Chief Scientist Office Conflicts of interest: none |
|
Cummings 2012‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; 1999‐2010 V: HPV vaccination status was verified through clinical records after enrolment (post‐vaccine group) O: self‐report (questionnaire) (study‐level targeted ascertainment) |
|
| Participants | N = 225 females 14 to 17 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Sexual activity (incidence of sexually transmitted infections); prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding:public/non‐profit: National Institutes of Health (NIH) Conflicts of interest: some authors received funding from the vaccine developer |
|
Cuschieri 2023‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom (Scotland); 2011‐2017 V: individual vaccination status not used. Pre‐/post‐vaccine analysis. O: 10 pathology laboratories in Scotland that serve 14 NHS territorial board areas |
|
| Participants | N = 1706 females 20 to 25 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | CIN3; CIN2+; CIN2 Follow‐up: not reported |
|
| Notes | Funding: the Scottish Government Conflicts of interest: none |
|
Deceuninck 2018‐CAN.
| Study characteristics | ||
| Methods | Cohort study Canada; October 1999‐March 2014 V: targeted for vaccination – no individual vaccination status data O: Quebec provincial hospital discharge database (national database) |
|
| Participants | N = 13,736,169 person‐years females and males 7 to 17 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Guillain‐Barré syndrome (GBS) Follow‐up: 15 years |
|
| Notes | Source of funding:public/non‐profit: Quebec Ministry of Health and Social Services Conflicts of interest: some authors received funding from the vaccine developer |
|
Dehlendorff 2018‐DNK/SWE.
| Study characteristics | ||
| Methods | Cohort study Denmark and Sweden; 2006‐2013 V: Swedish and Danish national health registry (national database) O: Swedish and Danish national health registry (national database) |
|
| Participants | N = not reported, females 13 to 30 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+ Follow‐up: 7 years |
|
| Notes | Source of funding: public/non‐profit: Mermaid Project (Mermaid 2), the Swedish Foundation for Strategic Research, the Swedish Research Council and the Swedish Cancer Society Conflicts of interest: some authors received funding from the vaccine developer |
|
Delere 2014‐DEU.
| Study characteristics | ||
| Methods | Cross‐sectional study Germany; October 2010‐September 2012 V: self‐report (questionnaire) O: self‐report; self‐sampling was performed by cervicovaginal lavage |
|
| Participants | N = 787 females 20 to 25 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Robert Koch Institute Conflicts of interest: some authors received expenses from the vaccine developer |
|
Del Mistro 2021‐ITA.
| Study characteristics | ||
| Methods | Cohort study Italy; January 2008‐December 2019 V: LHUs’ vaccination databases (regional database) O: screening programmes (national database) |
|
| Participants | N = 96,230 females 25 to 64 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; CIN3+; CIN2+; participation rates in screening Follow‐up: 12 years overall |
|
| Notes | Source of funding: public/non‐profit: Italian Ministry of Health Conflicts of interest: no |
|
DeSisto 2024‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; August 2018‐July 2023 V: medical records or registry data O: self‐ or clinician‐collected anal swab samples |
|
| Participants | N = 6350 MSM 18 to 45 years |
|
| Interventions | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Funding: Centers for Diseases Control and Prevention Conflict of interest: none |
|
De Souza 2023‐AUS.
| Study characteristics | ||
| Methods | Cross‐sectional study Australia; October 2020‐November 2021 V: Australian Immunisation Register O: oral saliva samples |
|
| Participants | N = 911 females and males 18 to 70 years |
|
| Interventions | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: private/industry: Merck & Co Conflicts of interest: none |
|
Dillner 2018‐EU.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Denmark, Sweden and Norway; 2006‐2013 V: no individual vaccination status O: national cervical screening registries |
|
| Participants | N = 12870 females 18 to 50 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: private/industry: Merck & Co Conflicts of interest: authors include employees of the vaccine developer |
|
Dominiak‐Felden 2015‐BEL.
| Study characteristics | ||
| Methods | Cohort study; pre‐ vs post‐vaccine introduction Belgium; January 2006 to December 2013 V: MLOZ database of reimbursements (insurance database) O: MLOZ database of reimbursements (insurance database) |
|
| Participants | N = 106,579 females and males Age (median) 19.3 |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 6 years |
|
| Notes | Source of funding: private/industry: Sanofi Pasteur MSD Conflicts of interest: authors include stockholders of the vaccine developer |
|
Donegan 2013‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction; self‐controlled case series United Kingdom; October 2008‐December 2011 V: Clinical Practice Research Datalink (national database) O: Clinical Practice Research Datalink (national database) |
|
| Participants | 161 cases of CFS/ME, females 12 to 20 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) Follow‐up: not reported |
|
| Notes | Source of funding:not reported Conflicts of interest: not reported |
|
Donken 2018‐NLD.
| Study characteristics | ||
| Methods | Cohort study Netherlands; 2009‐2016 V: national vaccination registration system, Praeventis O: self‐collected vaginal swab |
|
| Participants | N = 1635 females 20 to 23 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Incident HPV infection; persistent HPV infection Follow‐up: 6 years |
|
| Notes | Source of funding: public/non‐profit: Ministry of Health, Welfare, and Sport, the Netherlands Conflicts of interest: some authors received funding from the vaccine developer |
|
Donken 2021‐CAN.
| Study characteristics | ||
| Methods | Cohort; pre‐ vs post‐vaccine introduction Canada; 2004‐2017 V: individual vaccination status not used – pre‐/post‐introduction populations O: BC Cancer Cervix Screening Program Database (national database) |
|
| Participants | N = not reported, females attending cervical screening 16 to 28 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent), Gardasil 9 (Merck nonavalent) | |
| Outcomes | CIN3; CIN2+; CIN2 Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: Canadian Immunization Research Network (CIRN), the Michael Smith Foundation for Health Research (MSFHR), Canadian Institutes of Health Research (CIHR), BC Children's Hospital Foundation, and the Canadian Child Health Clinician Scientist Program Conflicts of interest: some authors received funding from the vaccine developer |
|
Dorton 2015‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; February 2007 to March 2014 V: self‐report O: electronic patient registry (hospital database) |
|
| Participants | N = 1392 females attending colposcopy ≤ 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; adenocarcinoma in situ; CIN2+ Follow‐up: cross‐sectional |
|
| Notes | Source of funding: not reported Conflicts of interest: not reported |
|
Elies 2022‐FRA.
| Study characteristics | ||
| Methods | Retrospective cohort study France; January 2006‐December 2016 V: French National Health Insurance database O: French National Health Insurance database |
|
| Participants | N = 42,452 females 19 to 30 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | |
| Outcomes | Treatment rates for CIN and other HPV‐related disease (conisation) Follow‐up: 10 years |
|
| Notes | Funding: none reported Conflicts of interest: none reported |
|
Enerly 2019‐NOR.
| Study characteristics | ||
| Methods | Cohort study Norway; September 2016‐February 2017 V: Norwegian Immunization Registry SYSVAK O: cervico‐vaginal and oral samples |
|
| Participants | N = 312 females 18 to 20 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 6 to 8 years after vaccination |
|
| Notes | Source of funding: public/non‐profit: Cancer Registry of Norway Conflicts of interest: some authors received funding from the vaccine developer |
|
Faber 2019‐DNK.
| Study characteristics | ||
| Methods | Cohort study Denmark; October 2006‐December 2014 V: Health Service Registry and the Danish Prescription Registry (national database) O: Medical Birth Registry and the National Patient Registry (national database) |
|
| Participants | N = 522,705 females Mean age (SD): 28 (4) years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Birth outcomes Follow‐up: 95 weeks |
|
| Notes | Source of funding:public/non‐profit: Mermaid project Conflicts of interest: some authors received funding from the vaccine developer |
|
Falcaro 2021‐GBR.
| Study characteristics | ||
| Methods | Cohort study United Kingdom; January 2006‐June 2019 V: no individual vaccination status. Age cohorts offered vaccination at specific ages or not offered vaccination. O: National Cancer Registration and Analysis Service, Public Health England (PHE) (national database) |
|
| Participants | N = not reported, females 20 to 64 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; CIN3 Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: Cancer Research UK Conflicts of interest: none |
|
Feder 2019‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; March 2012‐December 2014 V: self‐report O: self‐collected samples of vaginal cells |
|
| Participants | N = 375 females 21 to 29 years |
|
| Interventions | Not reported | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: National Institutes of Health NIH; U.S. Department of Health and Human Services, Health Resources and Services Administration’s Maternal and Child Health Bureau Conflicts of interest: none |
|
Feiring 2017‐NOR.
| Study characteristics | ||
| Methods | Cohort study Norway; 2009‐2014 V: Norwegian Immunisation Registry (national database) O: Norwegian Patient Registry (national database) |
|
| Participants | N = 176,453 females 11 to 17 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) Follow‐up: not reported |
|
| Notes | Funding: no specific funding Conflicts of interest: none |
|
Fernandes 2021‐PRT.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Portugal; May 2006‐December 2017 V: no individual vaccination status O: medical records of all male or female patients attending a first STD consultation (hospital database) |
|
| Participants | N = 28,354 females (attending sexual health clinic) Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 12 years |
|
| Notes | Source of funding: private/industry: Merck Sharp & Dohme Corp Conflicts of interest: unclear |
|
Flagg 2018‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; January 2006‐December 2014 V: no individual vaccination status O: MarketScan Commercial Claims and Encounters Database (Truven Health Analytics, Ann Arbor, MI) (national database) |
|
| Participants | N = 35,000,000 (88,911,951 person‐years) females and males 15 to 39 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: up to 9 years |
|
| Notes | Source of funding: unclear: both authors are with the Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention Conflicts of interest: not reported |
|
Frisch 2018‐DNK.
| Study characteristics | ||
| Methods | Cohort study Denmark; October 2006‐November 2016 V: Danish Vaccination Register (national database) O: Danish National Patient Register (national database) |
|
| Participants | N = 568,410 males 10 to 28 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Paralysis Follow‐up: 10 years |
|
| Notes | Source of funding:public/non‐profit: Danish Medicines Agency, Danish Cancer Society, Novo Nordisk Foundation Conflicts of interest: no |
|
Gargano 2021‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; 2009‐2016 V: Michigan Care Improvement Registry (regional database) O: Michigan Cancer Surveillance Program (national database) |
|
| Participants | N = 773,193 females Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+ Follow‐up: 8 years |
|
| Notes | Source of funding: public/non‐profit: Public Health Service Act and National Program of Cancer Registries Conflicts of interest: none |
|
Gargano 2023‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA, 2008‐2016 V: individual vaccination status not used – pre‐/post‐introduction populations O: HPV‐IMPACT study |
|
| Participants | N = 18,344 CIN2+ cases Female 20 to 39 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+; CIN3+ Follow‐up: up to 8 years |
|
| Notes | Funding: public/non‐profit: Centers for Disease Control and Prevention Emerging Infections Program Conflict of interest: one author received funding from the vaccine developer |
|
Garland 2018‐AUS.
| Study characteristics | ||
| Methods | Cohort study Australia; October 2011‐June 2015 V: self‐reported HPV vaccination details were verified with the National HPV Vaccination Program Register (NHVPR) O: self‐collected vaginal swab for HPV DNA detection and genotyping |
|
| Participants | N = 737 females 18 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: potentially to 8 years after vaccination |
|
| Notes | Source of funding: public/non‐profit: Victorian Cancer Agency Conflicts of interest: some authors received funding from the vaccine developer |
|
Goggin 2018‐CAN.
| Study characteristics | ||
| Methods | Cohort study Canada; March 2013‐July 2014 V: computer‐assisted questionnaire O: biological specimens were obtained by self‐sampling |
|
| Participants | N = 1550 females 17 to 29 years | |
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 5–6 years after HPV vaccination |
|
| Notes | Source of funding: public/non‐profit: Ministere de la Sante et des Services Sociaux du Quebec Conflicts of interest: some authors received funding from the vaccine developer |
|
Gonzalez 2020‐ARG.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Argentina; 2014‐2015; 2017‐2018 V: vaccination card, electronic clinical history or self‐report. Self‐reporting was the prevalent source of information. O: cervical cell samples |
|
| Participants | N = 2181 females 15 to 17 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Salud Investiga (“Carrillo‐O˜nativia” and “Abraam Sonis” fellowships), Direction de Control de Enfermedades Inmunoprevenibles and Instituto Nacional de Enfermedades Infecciosas‐ ANLIS Malbran, Ministerio de Salud de la Nacion Conflicts of interest: none |
|
Goodman 2024‐DEU.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Germany; January 2013‐December 2021 V: individual vaccination status not used – pre‐/post‐introduction populations O: Institut fur angewandte Gesundheitsforschung Berlin GmbH (InGef) research database |
|
| Participants | N = 22,533 (pre‐vaccine cohort); 38,987 (post‐vaccine cohort) 28 to 33 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | CIN2+, CIN2, CIN3, anogenital warts, cervical cancer Follow‐up: 15 years |
|
| Notes | Funding: for profit: Merck Sharp & Dohme LLC Conflicts of interest: authors are employees of vaccine manufacturer |
|
Grieger 2024‐DEU.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Germany; 2004‐2018 V: individual vaccination status not used – pre‐/post‐introduction populations O: German Center for Cancer Registry Data |
|
| Participants | N = 265,365 cases 18 to 35 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Cervical cancer | |
| Notes | Funding: not reported Conflicts of interest: none |
|
Grimaldi‐Bensouda 2017‐FRA.
| Study characteristics | ||
| Methods | Case‐control study France; April 2008‐October 2014 V: a tangible proof for HPV vaccination: vaccine batch number, vaccination booklet, prescription noted in health medical record, pharmacist's report, or any other type of certificate of HPV vaccination (study‐level targeted ascertainment) O: definite diagnosis of Guillain‐Barré syndrome at specialised centres across France (study‐level targeted ascertainment) |
|
| Participants | N = 143 cases of Guillain‐Barré syndrome, females 11 to 25 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Guillain‐Barré syndrome (GBS) Follow‐up: 6 years |
|
| Notes | Source of funding: private/industry: GlaxoSmithKline Biologicals SA Conflicts of interest: some authors received funding from the vaccine developer |
|
Gronlund 2016‐SWE.
| Study characteristics | ||
| Methods | Cohort study Sweden; October 2006‐December 2012 V: Swedish Voluntary Vaccination Register; Prescribed Drug Register (national database) O: National Patient Register (NPR) (national database) |
|
| Participants | N = 70,265 females 10 to 30 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Guillain‐Barré syndrome (GBS) Follow‐up: 6 years |
|
| Notes | Source of funding:public/non‐profit: Swedish Foundation for Strategic Research and the Strategic Research Area in Epidemiology (SfoEpi) Conflicts of interest: some authors received funding from the vaccine developer |
|
Guerra 2016‐CAN.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Canada; April 2003‐March 2013 V: no individual vaccination status O: Ontario Health Insurance Program (OHIP) (insurance database) |
|
| Participants | N = not reported, females 12 to 13 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 11 years |
|
| Notes | Source of funding: public/non‐profit Public Health Ontario; the Institute for Clinical Evaluative Sciences, Ontario Ministry of Health and Long‐Term Care Conflicts of interest: none |
|
Guo 2023‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; 2001‐2019 V: no individual vaccination status reported or used – pre‐/post‐vaccine analysis O: US Cancer Statistic Database (national database) |
|
| Participants | N = 8062 males and females 15 to 44 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; anal cancer; vulvar cancer; head and neck cancer; anal cancer; vaginal cancer Follow‐up: 18 years |
|
| Notes | Funding: The Cancer Prevention and Research Institute of Texas Conflict of interest: none |
|
Hariri 2018‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; August 2006‐September 2012 V: Kaiser Permanente electronic medical records (insurance database) O: Kaiser Permanente electronic medical records (insurance database) |
|
| Participants | N = 64,517 females (128,010 person‐years) 11 to 22 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: up to 6 years |
|
| Notes | Source of funding: public/non‐profit: Centers for Disease Control and Prevention Conflicts of interest: some authors received funding from the vaccine developer |
|
Harrison 2014‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; July 2000‐June 2012 V: no individual vaccination status O: randomly selected general practitioners (GPs), records |
|
| Participants | N = 1,175,879 encounters with patients, females Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Treatment rates for CIN and other HPV‐related disease Follow‐up: 12 years |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Australian Government Department of Health and Ageing, the Australian Government Department of Veterans’ Affairs, Australian Institute of Health and Welfare, National Prescribing Service, AstraZeneca Pty Ltd (Australia), Janssen‐Cilag Pty Ltd, Merck, Sharpe and Dohme (Australia) Pty Ltd, Pfizer Australia Pty Ltd, Abbott Australasia Pty Ltd, Sanofi‐Aventis Australia Pty Ltd, Wyeth Australia Pty Ltd, Novartis Pharmaceuticals Australia Pty Ltd, GlaxoSmithKline Australia Pty Ltd, Roche Products Pty Ltd, BioCSL Pty Ltd, Bayer Australia Ltd. Conflicts of interest: authors include employees of the vaccine developer |
|
Heard 2017‐FRA.
| Study characteristics | ||
| Methods | Cross‐sectional study France; 6 June 2014 to 25 March 2015 V: immunisation record O: the HPV analysis was performed on the residual material that remained after DNA extraction and analysis for C trachomatis. All samples were anonymised. |
|
| Participants | N = 2715 females 18 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Institut National du Cancer, Ville de Paris, SPILF (Société de pathologie infectieuse de langue Francaise) Conflicts of interest: no |
|
Herweijer 2016‐SWE.
| Study characteristics | ||
| Methods | Cohort study Sweden; January 2006‐December 2013 V: Swedish HPV Vaccination register; National Vaccination register; Prescribed Drug register (national databases) O: The National Swedish Cervical Screening Registry (NKCx); Swedish Cancer Register (national database) |
|
| Participants | N = 1,333,691 females 13 to 30 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN2+ Follow‐up: 8 years |
|
| Notes | Source of funding: mixed: Merck Sharp & Dohme; GlaxoSmithKline; Swedish Foundation for Strategic Research; Strategic Research Area in Epidemiology Conflicts of interest: some authors received funding from the vaccine developer |
|
Herweijer 2018‐SWE.
| Study characteristics | ||
| Methods | Cohort study; pre‐ vs post‐vaccine introduction Sweden; 2006‐2012 V: Statistics Sweden, Swedish Patient Register (national database) O: Swedish Patient Register, Prescribed Drug Register (national database) |
|
| Participants | N = 100,000 person‐years females and males 15 to 44 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: Swedish Foundation for Strategic Research Conflicts of interest: no |
|
Hikari 2022‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; April 2014‐March 2020 V: self‐report survey O: cervical cancer screening database, Saga Health Promotion Foundation |
|
| Participants | N = 7253 females 20 to 24 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+, CIN3+ Follow‐up: not reported |
|
| Notes | Funding: not reported Conflicts of interest: none |
|
Hiramatsu 2021‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; April 2011 – NR V: local government database or clinical record in the clinic or hospitals (regional databases) O: screening attendance (study‐level targeted ascertainment) |
|
| Participants | N = 1047 females attending cervical screening 20 to 21 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3; CIN2+; prevalent HPV infection Follow‐up: not reported, maximum would be 9 years (12 yo to 21 yo) |
|
| Notes | Source of funding: private/industry: Merck Sharp and Dohme Conflicts of interest: some authors received funding from the vaccine developer |
|
Hirth 2017‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; 2009‐2014 V: self‐report O: oral samples |
|
| Participants | N = 3040 females and males 18 to 30 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Office of Research on Women’s Health (ORWH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health Conflicts of interest: not reported |
|
Hoes 2021‐NLD.
| Study characteristics | ||
| Methods | Cohort study Netherlands; 2014‐2018 V: the national vaccination registry, Praeventis O: vaginal self‐sample |
|
| Participants | N = 2027 females 16 to 17 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Incident HPV infection Follow‐up: 4 years |
|
| Notes | Source of funding: public/non‐profit: Dutch Ministry of Health, Welfare and Sport Conflicts of interest: no |
|
Howell‐Jones 2013‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom (UK); 2002‐2011 V: no individual vaccination status. Data on 3‐dose coverage achieved by the National HPV Immunisation Programme for each academic year (September to August) and Primary Care Trust (PCT) were obtained from published reports. O: diagnoses of STIs made at GUM clinics in England are reported to Public Health England (national database) |
|
| Participants | N = not reported, females (attending sexual health clinic) 15 to 24 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Anogenital warts Follow‐up: repeated cross‐sectional 2002‐2011 |
|
| Notes | Source of funding: public/non‐profit: Medicines and Healthcare products Regulatory Agency (MHRA); NHS National Institute for Health Research (NIHR) Conflicts of interest: authors include stockholders of the vaccine developer |
|
Huyghe 2023‐BEL.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Belgium; 2010‐2019 V: no individual vaccination status used O: Algemeen Medisch Labo (AML) in Antwerp |
|
| Participants | N = 3008 females 20 to 23 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 9 years |
|
| Notes | Source of funding: none Conflict of interest: none |
|
Hviid 2017‐DNK/SWE.
| Study characteristics | ||
| Methods | Cohort study Denmark, Sweden; October 2006‐June 2013 V: National vaccination registers : Childhood Vaccination Database (Denmark), Swedish HPV vaccination register; national prescription registers (national databases) O: hospital patient registers (national databases) |
|
| Participants | N = 3,126,790 females 18 to 44 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Paralysis; Guillain‐Barré syndrome (GBS) Follow‐up: 7 years |
|
| Notes | Source of funding: public/non‐profit: Novo Nordisk Foundation; SFO, Karolinska Institutet; Danish Medical Research Council Conflicts of interest: some authors received funding from the vaccine developer |
|
Hviid 2020‐DNK.
| Study characteristics | ||
| Methods | Self‐controlled case series Denmark; January 2007‐December 2016 V: Danish Vaccination Register (national database) O: Danish National Patient Register (national database) |
|
| Participants | N = 1,375,737 females; 198 cases of POTS 10 to 44 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Postural orthostatic tachycardia syndrome (POTS); chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME); complex regional pain syndrome (CRPS) Follow‐up: 10 years |
|
| Notes | Source of funding: public/non‐profit: Danish Medicines Agency; Danish Cancer Society; Novo Nordisk Foundation Conflicts of interest: no |
|
Hviid 2021‐DNK.
| Study characteristics | ||
| Methods | Cohort study Denmark; October 2020‐January 2021 V: Danish vaccination register (national database) O: Danish National Patient Registry (national database) |
|
| Participants | N = 996,300 females 11 to 34 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Primary ovarian insufficiency Follow‐up: not reported |
|
| Notes | Source of funding: private/industry: Novo Nordisk Foundation Conflicts of interest: no |
|
Ikeda 2021‐JPN.
| Study characteristics | ||
| Methods | Case‐control study Japan; April 2013‐March 2017 V: municipality immunisation records (regional database) O: screening (study‐level targeted ascertainment) |
|
| Participants | N = 12,513 females attending cervical screening 20 to 24 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; CIN3+; CIN3; CIN2+; CIN2 Follow‐up: 4 years |
|
| Notes | Source of funding: public/non‐profit: The Ministry of Health, Labor, and Welfare, Japan; the Japan Agency for Medical Research and Development Conflicts of interest: some authors received funding from the vaccine developer |
|
Innes 2020‐NZL.
| Study characteristics | ||
| Methods | Cohort study New Zealand; 2010‐2015 V: New Zealand National Immunisation Register (NIR) (national database) O: National Cervical Screening Programme (NCSP) (national database) |
|
| Participants | N = 104,313 females 20 to 24 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+ Follow‐up: up to 5 years |
|
| Notes | Source of funding: not reported Conflicts of interest: no |
|
Jacot‐Guillarmod 2017‐CHE.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Switzerland; 2013 V: self‐report O: self‐collected cervicovaginal sample |
|
| Participants | N = 690 females 18 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, up to 5 years after vaccination |
|
| Notes | Source of funding: public/non‐profit: University of Lausanne ; Public Health Office of the canton of Vaud Conflicts of interest: no |
|
Jeannot 2018‐CHE.
| Study characteristics | ||
| Methods | Cross‐sectional study Switzerland; January 2016 and October 2017 V: self report O: self sampling procedure |
|
| Participants | N = 409 females 24 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Funding source: no specific funding Conflicts of interest: no |
|
Jemal 2013‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; 1975‐2009 V: National Immunization Survey‐Teen (NIS‐Teen) (survey) O: CDC’s National Program of Cancer Registries (NPCR) and/or the NCI’s Surveillance, Epidemiology, and End Results (SEER) program, CDC National Center for Health Statistics’ National Vital Statistics System (national database) |
|
| Participants | N = not reported (population estimates as of July 1 of each year), females Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; vaginal cancer; vulval cancer; anal cancer; penile cancer; head and neck cancer Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: the American Cancer Society, the Centers for Disease Control and Prevention, the National Cancer Institute, the National Institutes of Health, and the North American Association of Central Cancer Registries Conflicts of interest: not reported |
|
Jena 2015‐USA.
| Study characteristics | ||
| Methods | Cohort study USA, January 2005‐December 2010 V: data on all pharmacy and medical claims from 41 large employers across the United States (routine administrative database, insurance) O: data on all pharmacy and medical claims from 41 large employers across the United States (routine administrative database, insurance) |
|
| Participants | N = 21610 females 12 to 18 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Sexual activity (incidence of sexually transmitted infections) Follow‐up: 6 years |
|
| Notes | Source of funding: public/non‐profit: National Institutes of Health (Early Independence Award); National Institute of Aging Conflicts of interest: no |
|
Judlin 2016‐FRA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction France; December 2008‐March 2012 V: no individual vaccination status O: AGW cases prospectively recorded by gynaecologists (study‐level targeted ascertainment) |
|
| Participants | N = 84818 females (attending sexual health clinic) 15 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional |
|
| Notes | Source of funding: private/industry: Sanofi Pasteur MSD Conflicts of interest: authors include employees of the vaccine developer |
|
Kahn 2016‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐ vaccine introduction USA; 2006‐2014 V: review of electronic medical records and Ohio statewide immunisation registry data O: cervicovaginal testing for HPV |
|
| Participants | N = 1180 females 13 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, repeated at 0, 3 and 7 years |
|
| Notes | Source of funding: public/non‐profit: National Institute of Allergy and Infectious Diseases, National Institutes of Health Conflicts of interest: some authors received funding from the vaccine developer |
|
Kalliala 2021‐FIN.
| Study characteristics | ||
| Methods | RCT extension Finland; 2007‐2014 V: HPV‐040 trial records ; Finnish Medical Drug Agency O:Finnish Medical Birth Registry |
|
| Participants | N = 27845 females 15 to 22 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Birth outcomes Follow‐up: up to 7 years |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Academy of Finland; Finnish Cancer Organizations; EU FP7; IMI networks PREHDICT and CoheaHR; ADVANCE; GlaxoSmithKline Biologicals SA; Helsinki Uusimaa Hospital District, Academy of Finland; Jalmari and Rauha Ahokas Foundation; Paulo Foundation Conflicts of interest: some authors received funding from the vaccine developer |
|
Katz 2021‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; June 2011‐April 2020 V: medical records (hospital database) O: medical records (hospital database) |
|
| Participants | N = 1,310,334 females and males 0 to 84 years |
|
| Interventions | Gardasil (Merck quadrivalent), Gardasil 9 (Merck nonavalent) | |
| Outcomes | Head and neck cancer Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: National Center for Advancing Translational Sciences of the National Institutes of Health Conflicts of interest: no |
|
Khoo 2022‐MYS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Malaysia; 2013‐2020 V: self‐report O: self sampling procedure |
|
| Participants | N = 1577 females 18 to 24 and 35 to 45 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Funding: private/industry: vaccine manufacturer Conflict of interest: some authors received funding from the vaccine developer |
|
Kitamura 2023‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; April 2017‐March 2020 V: self‐report O: self‐sampling procedure |
|
| Participants | N = 2044 females 16 to 75 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Funding: Japanese Foundation for Sexual Health Medicine Conflicts of interest: none |
|
Kjaer 2020‐EU.
| Study characteristics | ||
| Methods | RCT extension Denmark, Iceland, Norway, Sweden; June 2002‐March 2017 V: vaccinated: FUTURE II trial vaccine recipient (per‐protocol population); unvaccinated population constructed from Nordic national registries and a cohort study O: national registries |
|
| Participants | N = not reported, females 23 to 29 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+ Follow‐up: 14 years |
|
| Notes | Source of funding: private/industry: Merck Sharp & Dohme Corp Conflicts of interest: authors include employees of the vaccine developer |
|
Kjaer 2021‐DNK.
| Study characteristics | ||
| Methods | Cohort study Denmark; October 2006‐December 2019 V: National Health Service register and National Prescription registry (national database) O: Danish pathology registry (national database) |
|
| Participants | N = 867,689 females < 17, 17 to 19, 20 to 30 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent), Gardasil 9 (Merck nonavalent) | |
| Outcomes | Cervical cancer Follow‐up: up to 13 years |
|
| Notes | Source of funding: public/non‐profit: Mermaid project (Mermaid 2) Conflicts of interest: some authors received funding from the vaccine developer |
|
Kjaer 2021‐EU.
| Study characteristics | ||
| Methods | Cohort study Denmark, Norway, Sweden; 2004‐2017 V: vaccinated participants randomised to 9‐valent vaccine in a previous RCT; unvaccinated participants are historic pre‐HPV‐vaccine controls O: national screening registries |
|
| Participants | N = not reported, females 23 to 29 years |
|
| Interventions | Gardasil 9 (Merck nonavalent) | |
| Outcomes | CIN2+ Follow‐up: 8 years |
|
| Notes | Source of funding: private/industry: Merck Sharp & Dohme Conflicts of interest: authors include employees of the vaccine developer |
|
Krasnopolsky 2020‐RUS.
| Study characteristics | ||
| Methods | Cross‐sectional study Russia; study dates: not reported V: not reported O: hospital observation (study‐level targeted ascertainment) |
|
| Participants | N = 440 females 18 to 36 years |
|
| Interventions | Not reported | |
| Outcomes | Birth outcomes; anogenital warts Follow‐up: not reported |
|
| Notes | Source of funding: not reported Conflicts of interest: not reported |
|
Kreimer 2011‐CRI.
| Study characteristics | ||
| Methods | RCT extension Costa Rica; June 2004‐August 2017 V: Costa Rica Vaccine Trial records O: Costa Rica Vaccine Trial extension (study‐level targeted ascertainment) |
|
| Participants | N = 6563 female trial participants, community controls 26 to 38 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Birth outcomes; CIN3+; CIN2+; incident HPV infection; prevalent HPV infection Follow‐up: 11 years |
|
| Notes | Source of funding: mixed: public/non‐profit and private/industry: US National Cancer Institute; National Institutes of Health; GlaxoSmithKline Biologicals (GSK) Conflicts of interest: authors include stock holders of the vaccine developer |
|
Kudo 2019‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; 2014‐2016 V: municipal records archived at public health centres in addition to self‐report O: residual samples from liquid‐based cytologic analysis (SurePath BD Diagnostics, Sparks, MD) during cervical screening were collected and underwent HPV genotyping. |
|
| Participants | N = 4553 females 20 to 26 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: Health and Labor Sciences (Ministry of Health, Labor and Welfare); Japanese Agency for Medical Research and Development (AMED) Conflicts of interest: some authors received funding from the vaccine developer |
|
Kumakech 2016‐UGA.
| Study characteristics | ||
| Methods | Cross‐sectional study Uganda; July 2014‐August 2014 V: 2008 HPV vaccination register O: cervical swabs; interviewer‐administered questionnaire |
|
| Participants | N = 488 females 15 to 24 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 5.5 years post vaccine |
|
| Notes | Source of funding: public/non‐profit: Swedish International Development Cooperation Agency (SIDA) Conflicts of interest: no |
|
Kury 2013‐BRA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Brazil; 2007‐2012 V: no individual vaccination status O: National System of Notification (SINAN) of Brazilian Ministry of Health (national database) |
|
| Participants | N = not reported, females < 21 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: maximum 2 years |
|
| Notes | Source of funding: public/non‐profit: Secretariat of Health of the Municipality of Campos dos Goytacazes, Rio de Janeiro, Brazil Conflicts of interest: not reported |
|
Laake 2020‐NOR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Norway; 2011‐2014 V: Norwegian Immunization Registry O: urine samples |
|
| Participants | N = 11,828 females 17 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, 5 years after vaccination |
|
| Notes | Source of funding: public/non‐profit: Norwegian Institute of Public Health and the Norwegian Ministry of Health and Care Services Conflicts of interest: no |
|
Latsuzbaia 2019‐LUX.
| Study characteristics | ||
| Methods | Cross‐sectional study Luxembourg; November 2015‐December 2017 V: social security records, self‐report O: cervical samples |
|
| Participants | N = 716 females 18 to 29 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, longest follow‐up since vaccination 17 years |
|
| Notes | Source of funding: public/non‐profit: Fonds National de la Recherche Luxembourg Conflicts of interest: no |
|
Lee 2022‐THA.
| Study characteristics | ||
| Methods | Retrospective cohort study Thailand; November 2018‐July 2019 V: registry departments of 5 institutes/hospitals O: electronic medical records |
|
| Participants | N = 993 20 to 45 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 5 years |
|
| Notes | Source of funding: National Vaccine Institute, Ministry of Public Health, Thailand Conflicts of interest: none |
|
Lehtinen 2017a‐FIN.
| Study characteristics | ||
| Methods | Cross‐sectional study Finland; 2010‐2014 V: The extracted, pseudonymised DNA samples were identified as being from an HPV‐16/18–vaccinated, a hepatitis B virus–vaccinated, or an unvaccinated participant. O: The extracted DNA from the FVU samples was analysed using a polymerase chain reaction. |
|
| Participants | N = not reported, males 18 years |
|
| Interventions | Not reported | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Academy of Finland, EU FP7, and IMI networks PREHDICT and CoheaHR, and ADVANCE Conflicts of interest: some authors received funding from the vaccine developer |
|
Lehtinen 2017b‐FIN.
| Study characteristics | ||
| Methods | Cohort study Finland; May 2004‐December 2014 V: Finnish Population Register Centre (national database) O: Finnish Cancer Registry; questionnaire on life habits with special emphasis on sexual health (national database, routine administrative database, national) |
|
| Participants | N = 18,137 female trial participants, community controls 22 to 28 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | CIN3+ Follow‐up: up to 10 years |
|
| Notes | Source of funding: mixed: public/non‐profit and private/industry: GlaxoSmithKline Biologicals SA (Belgium), Academy of Finland, Finnish Cancer Organizations and the Swedish Cancer Society Conflicts of interest: authors include employees of the vaccine developer |
|
Lei 2020a‐SWE.
| Study characteristics | ||
| Methods | Cohort study Sweden; January 2006‐December 2017 V: Swedish HPV Vaccination Register, the Prescribed Drug Register, and the National Vaccination Register (national database) O: Swedish Cancer Register (national database) |
|
| Participants | N = 1,672,983 females 10 to 30 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN2+ Follow‐up: up to 12 years |
|
| Notes | Source of funding: public/non‐profit: Swedish Foundation for Strategic Research; Swedish Cancer Society; Swedish Research Council; China Scholarship Council Conflicts of interest: some authors received funding from the vaccine developer |
|
Lei 2020b‐SWE.
| Study characteristics | ||
| Methods | Cohort study Sweden; 2008‐December 2017 V: Swedish HPV Vaccination Register; Prescribed Drug Register (national database) O: Swedish National Cervical Screening Registry (national database) |
|
| Participants | N = 153,250 females attending cervical screening 10 to 30 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: CoheaHr; Swedish Foundation for Strategic Research; Swedish Cancer Society; Swedish Research Council; China Scholarship Council Conflicts of interest: some authors received funding from the vaccine developer |
|
Liu 2014‐AUS.
| Study characteristics | ||
| Methods | Cross‐sectional study; pre‐ vs. post‐vaccine introduction Australia; 2001‐2011 V: no individual vaccination status; eligibility for vaccine determined by date of survey and age O: self‐report by telephone survey |
|
| Participants | N = 7225 females 18 to 39 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 10 years |
|
| Notes | Source of funding: public/non‐profit: Australian National Health and Medical Research Council (NHMRC); Victorian Cytology Service Conflicts of interest: authors include stockholders of the vaccine developer |
|
Loenenbach 2023‐DEU.
| Study characteristics | ||
| Methods | Cross‐sectional study Germany; June 2017‐January 2018 V: self‐report O: self‐sampling kit |
|
| Participants | N = 1226 females 20 to 25 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Federal Ministry of Health of Germany (Bundesministerium für Gesundheit) Conflicts of interest: none |
|
Lopez 2018‐ESP.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Spain; 2003‐2014 V: individual vaccination status not used – pre‐/post‐introduction O: national surveillance system for hospital data (CMBD) (national database) |
|
| Participants | N = not reported, females All ages |
|
| Interventions | Not reported | |
| Outcomes | Cervical cancer; adenocarcinoma in situ Follow‐up: 12 years |
|
| Notes | Funding: no specific funding Conflicts of interest: some authors received funding from the vaccine developer |
|
Lukac 2020‐CAN.
| Study characteristics | ||
| Methods | Pre‐ vs post‐ vaccine introduction Canada; January 2000‐December 2017 V: no individual vaccination status O: system (STI‐IS) – electronic medical record system used at STI clinics (regional database) |
|
| Participants | N = 78,588 females and males (WSM, MSW and MSM) 1) 20 years or less; 2) 21 to 23 years; 3) 28 years or less |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: mean person‐year per individual (SD): 1.90 y (2.26) |
|
| Notes | Funding: no specific funding Conflicts of interest: no |
|
Luostarinen 2018‐FIN.
| Study characteristics | ||
| Methods | RCT extension Finland; June 2007‐December 2015 V: RCT records O: Finnish Cancer Registry (national database) |
|
| Participants | N = 27,367 female trial participants, community controls Age not reported |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; vulvar cancer; head and neck cancer Follow‐up: 7 years |
|
| Notes | Source of funding: mixed: public/non‐profit and private/industry: Academy of Finland, Cancer Society of Finland, GSK Biologicals SA, Nordic Cancer Union Conflicts of interest: some authors received funding from the vaccine developer |
|
Lurie 2017‐ISR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Israel; 2006‐2015 V: Maccabi Healthcare Services database (insurance database) O: Maccabi Healthcare Services database (insurance database) |
|
| Participants | N = not reported, females Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: not reported, study periods assumed at least 1 year lag to observe vaccine effect |
|
| Notes | Source of funding: not reported Conflicts of interest: some authors received expenses from the vaccine developer |
|
Lynge 2020‐DNK.
| Study characteristics | ||
| Methods | Pre‐ vs. post vaccine introduction Denmark; 2017‐2019 V: unclear O: HPV testing for the study embedded in routine cytology examination for cervical screening |
|
| Participants | N = not reported, females 23 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Danish Health Foundation, Det Frie Forskningsråd; HPV‐DNA test‐kits for the study were provided free of charge by Roche Conflicts of interest: no |
|
Ma 2017‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; October 2010‐May 2012 V: self‐report O: self‐collected vaginal samples for HPV DNA testing |
|
| Participants | N = 164 females 18 to 24 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Incident HPV infection Follow‐up: 1 year (mean) |
|
| Notes | Source of funding: public/non‐profit: National Institutes of Health Conflicts of interest: no |
|
Machalek 2018‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; 2005‐2015 V: National HPV Vaccination Program Register O: 1 mL of the PreservCyt specimen was tested for the presence of 14 high‐risk HPV types using the cobas HPV test |
|
| Participants | N = 656 females 18 to 35 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, 8 years apart |
|
| Notes | Source of funding: public/non‐profit: Australian Government Department of Health HPV Surveillance Fund Conflicts of interest: authors include stockholders of the vaccine developer |
|
Mann 2019‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; January 2010‐December 2016 V: no individual vaccination status O: Centers for Disease Control and Prevention’s STD Surveillance Network (SSuN) (study‐level targeted ascertainment) |
|
| Participants | N = 653,847 females and males (attending sexual health clinic) All ages |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional, repeated over 7 years |
|
| Notes | Source of funding: unclear Conflicts of interest: no |
|
Markowitz 2019‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; 2007, 2012‐2013, 2015‐2016 V: Kaiser Permanente database O: cytology samples |
|
| Participants | N = 12,788 females 20 to 29 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Centers for Disease Control and Prevention Conflicts of interest: some authors received funding from the vaccine developer |
|
Markowitz 2020‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; June 2006‐February 2017 V: Kaiser Permanente medical insurance records O: Kaiser Permanente medical insurance records |
|
| Participants | N = 4269 females 20 to 29 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 11 years |
|
| Notes | Source of funding: public/non‐profit: Centers for Disease Control and Prevention Conflicts of interest: some authors received funding from the vaccine developer |
|
Martellucci 2022‐ITA.
| Study characteristics | ||
| Methods | Retrospective cohort study Italy; January 2015‐June 2020 V: local health agency registry O: local health agency registry |
|
| Participants | N = 4665 females 25 to 30 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+ Follow‐up: up to 5 years |
|
| Notes | Funding: public/non‐profit: Italian Ministry of Health center for disease control and prevention Conflicts of interest: no |
|
Martin‐Merino 2021‐ESP.
| Study characteristics | ||
| Methods | Cohort study Spain; January 2007‐December 2016 V: Spanish Primary Care Database for Pharmacoepidemiological Research (national database) O: Spanish Primary Care Database for Pharmacoepidemiological Research (national database) |
|
| Participants | N = 388,849 females 9 to 28 years |
|
| Interventions | Not reported | |
| Outcomes | Guillain‐Barré syndrome (GBS) Follow‐up: 10 years |
|
| Notes | Source of funding:public/non‐profit: Instituto de Salud Carlos III (Co‐funded by European Regional Development Fund) Conflicts of interest: no |
|
McDaniel 2020‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; 2011‐2014 V: self‐report O: oral samples |
|
| Participants | N = 822 females and males 30 to 33 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: not reported Conflicts of interest: no |
|
McGregor 2018‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; 2005‐2015 V: Australian National HPV Vaccination Program Register (NHVPR) O: laboratory methods for HPV genotype detection |
|
| Participants | N = 297 females 18 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Australian Government Department of Health Conflicts of interest: some authors received funding from the vaccine developer |
|
McInerney 2017‐USA.
| Study characteristics | ||
| Methods | Cohort study United States of America (USA); 2013‐2017 V: self‐report O: self‐report (study‐level targeted ascertainment) |
|
| Participants | N = 4505 females and males Mean age: 25 to 32 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Infertility Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Danish Cancer Society Conflicts of interest: not reported |
|
Mehanna 2019‐GBR.
| Study characteristics | ||
| Methods | Cross‐sectional study United Kingdom (UK); 2013‐2015 V: regional health authorities O: oral samples (oral rinse, either of the oral brushes, or the tonsillar tissue samples) |
|
| Participants | N = 212 females and males 12 to 24 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: private/industry: GlaxoSmithKline Biologicals SA (GSK) Conflicts of interest: authors include employees of the vaccine developer |
|
Mesher 2018‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom (UK); 2010‐2016 V: data obtained from laboratories from the chlamydia test request form; data obtained by linkage with local Child Health Information Service (CHIS) Systems O: vulva‐vaginal swab specimens |
|
| Participants | N = 2318 females 16 to 24 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Public Health England Conflicts of interest: some authors received funding from the vaccine developer |
|
Miranda 2017‐FRA.
| Study characteristics | ||
| Methods | Cohort study France; January 2008‐December 2013 V: French national health insurance anonymised claim database (SNIIRAM)/national hospital discharge database (PMSI) (national database) O: French national health insurance anonymised claim database (SNIIRAM)/national hospital discharge database (PMSI) (national database) |
|
| Participants | N = 2,252,716 females 13 to 17 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Guillain‐Barré syndrome (GBS) Follow‐up: mean 33 months |
|
| Notes | Source of funding: not reported Conflicts of interest: no |
|
Mix 2022‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; 2000‐2017 V: no individual vaccine status O: Surveillance, Epidemiology, and End Results (SEER) Program ‐ 18 central cancer registries covering 27.8% of the U.S. population |
|
| Participants | N = not reported, females 15 to 39 years |
|
| Interventions | Not reported | |
| Outcomes | VaIN; VIN; AIN Follow‐up: 17 years |
|
| Notes | Source of funding: public/non‐profit: Oak Ridge Institute for Science and Education, an asset of the U.S. Department of Energy. Conflicts of interest: not reported |
|
Munoz‐Quiles 2021‐ESP.
| Study characteristics | ||
| Methods | Cohort study Spain; January 2009‐December 2017 V: Vaccine Information System (VIS); The Valencia healthcare Integrated Databases (VID) (national, regional database) O: The Valencia healthcare Integrated Databases (VID) (national, regional database) |
|
| Participants | N = 563,240 females 14 to 23 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 9 years |
|
| Notes | Source of funding: private/industry: MSD Conflicts of interest: some authors received funding from the vaccine developer |
|
Munro 2017‐GBR.
| Study characteristics | ||
| Methods | Cross‐sectional study United Kingdom (UK); December 2012‐November 2014 V: self‐report (verified by the Scottish Cervical Call Recall System (SCCRS)) O: colposcopy results following an abnormal cytology result at routine cervical screening (national database) |
|
| Participants | N = 163 females attending colposcopy 20 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3; CIN2+; CIN2 Follow‐up: mean age last dose: 17.3; mean age colposcopy: 22 |
|
| Notes | Source of funding: public/non‐profit: Chief Scientist Office, Scotland; NHS; The Jean Shanks Foundation Conflicts of interest: no |
|
Muresu 2022‐ITA.
| Study characteristics | ||
| Methods | Cross‐sectional study Italy; March 2016‐December 2020 V: self‐report O: regional Pap screening programme, Sassari |
|
| Participants | N = 1186 females 25 to 64 years |
|
| Interventions | Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | CIN2+ Follow‐up: cross‐sectional |
|
| Notes | Funding: none Conflict of interest: none |
|
Naleway 2020‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; January 2000‐December 2016 V: no individual vaccination status O: Kaiser Permanente Northwest electronic medical record system (insurance database) |
|
| Participants | N = 565,356 females and males 11 to 39 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional, repeated over 16 years |
|
| Notes | Source of funding: public/non‐profit: US Centers for Disease Control and Prevention Conflicts of interest: no |
|
Napolitano 2024‐ITA.
| Study characteristics | ||
| Methods | Cross‐sectional study Italy, November 2022 – September 2023 V: self‐report O: self‐sampling saliva and urine samples |
|
| Participants | N = 1002 males and females 18 to 30 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent), Gardasil 9 (Merck nonavalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Italian Ministry of University and Research Conflicts of interest: none |
|
Nilyanimit 2024‐THA.
| Study characteristics | ||
| Methods | Cross‐sectional study Thailand; 2023 V: defined by location, school vaccination programme O: self‐sampled urine |
|
| Participants | N = 587 females 16 to 18 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 7 years |
|
| Notes | Source of funding: National Research Council of Thailand, Health Systems Research Institute, the Center of Excellence in Clinical Virology at Chulalongkorn University, Kind Chulalongkorn Memorial Hospital, the MK Restaurant Group and Aunt Thongkham Foundation, the Department of Disease Control and the Education and Public Welfare Foundation Conflicts of interest: none |
|
Nsouli‐Maktabi 2013‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; January 2000‐December 2012 V: no individual vaccination status O: the Defense Medical Surveillance System (DMSS) (insurance database) |
|
| Participants | N = 1,544,029 (2000), 1,440,362 (2012) females and males (armed forces) Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional, repeated over 13 years |
|
| Notes | Source of funding: not reported Conflicts of interest: not reported |
|
Nygard 2023‐NOR.
| Study characteristics | ||
| Methods | Retrospective cohort study/database linkage Norway; January 2006‐December 2016 V: Norwegian Immunisation Registry O: Norwegian Prescription Database and the Norwegian Patient Registry |
|
| Participants | N = 2,187,724 males and females 13 to 31 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 3 years |
|
| Notes | Funding: not reported Conflicts of interest: some authors received funding from the vaccine developer |
|
Oliphant 2011‐NZL.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction New Zealand; January 2007‐June 2010 V: no individual vaccination status O: Auckland Sexual Health Service (hospital database) |
|
| Participants | N = 40,793 females and males (attending sexual health clinic) Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional repeated |
|
| Notes | Source of funding: not reported Conflicts of interest: no | |
Onuki 2023‐JPN.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Japan; 1975‐2020 V: individual vaccination status not used – pre‐/post‐vaccine introduction O: nationwide hospital‐based cancer registry |
|
| Participants | N = 418,918 cases of cervical cancer in females 20+ years of age |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer | |
| Notes | Funding: Japan Agency for Medical Research and Development Conflicts of interest: none |
|
Orumaa 2020‐NOR/DNK.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Norway and Denmark; 2006–2015 V: The Norwegian Immunization Registry (SYSVAK); The Danish National Prescription Registry (national databases) O: The Norwegian Patient Registry; The Norwegian Prescription Database; The Danish National Patient Register; The Danish National Prescription Registry; The Danish National Health Service Register (national databases) |
|
| Participants | N = 30,866,417 person‐years females and males 12 to 35 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional (repeated yearly) |
|
| Notes | Funding: no specific funding Conflicts of interest: some authors received funding from the vaccine developer |
|
Orumaa 2024‐NOR.
| Study characteristics | ||
| Methods | Retrospective cohort study/database linkage Norway; January 2007‐December 2020 V: Norwegian Immunization Registry O: Norwegian Cervical Cancer Screening Program |
|
| Participants | N = 868,403 females 16 to 30 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+; CIN3+ Follow‐up: 11 years |
|
| Notes | Funding: MSD (Norge) AS (grant to the Cancer Registry of Norway) Conflict of interest: some authors are employees and others received grants from the vaccine developer |
|
Osmani 2022‐DEU.
| Study characteristics | ||
| Methods | Retrospective cohort study Germany; 2008‐2018 V: Bavarian Association of Statutory Health Insurance Physicians O: Bavarian Association of Statutory Health Insurance Physicians |
|
| Participants | N = 433,346 females 19 to 28 years |
|
| Interventions | Gardasil (Merck quadrivalent); Cervarix (GSK bivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Anogenital warts Follow‐up: 10 years |
|
| Notes | Funding: Open Access funding enabled and organised by Projekt DEAL Conflicts of interest: none |
|
Ounchanum 2024‐THA/VNM.
| Study characteristics | ||
| Methods | Prospective cohort study Thailand/Vietnam; 2013‐2018 V: self‐report O: anogenital sampling |
|
| Participants | N = 192 females 12 to 24 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Persistent HPV infection Follow‐up: 3 years |
|
| Notes | Source of funding: US National Institute of Health Conflicts of interest: none |
|
Ozawa 2017‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; April 2014‐March 2016 V: self‐report O: Miyagi Cancer Society (regional database) |
|
| Participants | N = 5924 females attending cervical screening 20 to 24 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN2+ Follow‐up: median about 7 years post‐vaccination (0 to 4 weeks between the 2 visits) |
|
| Notes | Source of funding: not reported Conflicts of interest: no |
|
Palmer 2019‐GBR.
| Study characteristics | ||
| Methods | Cohort study United Kingdom (UK); 2008‐2016 V: Scottish Immunisation Call‐Recall System (national database) O: Information Services Division (ISD) of the Scottish National Health Service (national database) |
|
| Participants | N = not reported, females attending cervical screening 20 to 21 years | |
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | CIN3+; CIN2; prevalent HPV infection Follow‐up: up to 6 years |
|
| Notes | Source of funding:public/non‐profit: Health Protection Scotland, a part of the Scottish National Health Service Conflicts of interest: some authors received expenses from the vaccine developer |
|
Palmer 2024‐GBR.
| Study characteristics | ||
| Methods | Retrospective cohort study/database linkage United Kingdom (UK); 2020 V: Scottish Cervical Cancer Call Recall System (national database) O: Scottish Cancer Registry (national database) |
|
| Participants | N = 447,845 females 24 to 32 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Cervical cancer Follow‐up: up to 12 years |
|
| Notes | Funding: Scottish government through core funding of Public Health Scotland Conflicts of interest: none |
|
Paraskevaidis 2020‐GRC.
| Study characteristics | ||
| Methods | Cohort study Greece; 2009‐2019 V: not reported O: all colposcopic evaluations were performed in each department |
|
| Participants | N = 1698 females Age not reported |
|
| Interventions | Not reported | |
| Outcomes | CIN3; CIN2; treatment rates for CIN and other HPV‐related disease Follow‐up: not reported |
|
| Notes | Source of funding: not reported Conflicts of interest: no |
|
Perkins 2015‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; 2004‐2013 V: electronic medical record (hospital database) O: administrative data (hospital database) |
|
| Participants | N = 45,787 females and males (primary health care) 16 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional, repeated over 9 years |
|
| Notes | Source of funding: public/non‐profit: American Cancer Society Conflicts of interest: no |
|
Perkins 2017‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; January 2007‐December 2013 V: Truven Health Analytics Marketscan Commercial Claims Database (insurance database) O: Truven Health Analytics Marketscan Commercial Claims Database (insurance database) |
|
| Participants | N = 387,906 females 9 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: average 5.64 years |
|
| Notes | Source of funding: public/non‐profit: American Cancer Society Conflicts of interest: no |
|
Petras 2015‐CZE.
| Study characteristics | ||
| Methods | Cross‐sectional study Czech Republic; January 2013‐March 2014 V: self‐administered questionnaire (study‐level targeted ascertainment) O: self‐administered questionnaire (study‐level targeted ascertainment) |
|
| Participants | N = 19199 females (primary health care) 16 to 40 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: not reported |
|
| Notes | Source of funding: not reported Conflicts of interest: some authors received lecture fees from a vaccine developer |
|
Purrinos‐Hermida 2018‐ESP.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Spain; 2008‐2017 V: electronic clinical history/questionnaire O: self‐filled questionnaire/cervical scrapings |
|
| Participants | N = 1268 females 18 to 26 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Direccion xeral de Saude Publica Edificio Administrativo S. Lazaro s/n Santiago de Compostela (Galicia ‐ Spain) Conflicts of interest: no |
|
Rana 2013‐FIN.
| Study characteristics | ||
| Methods | RCT extension Finland; 2006‐2012 V: RCT records O: Finnish Cancer Registry (national database) |
|
| Participants | N = 16,584 females (trial participants, community controls) 20 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; CIN3 Follow‐up: up to 9 years after vaccination |
|
| Notes | Source of funding: mixed: public/non‐profit and private/industry: Finnish Cancer Organizations and Nordic Cancer Union, Merck & Co. Inc., GSK Biologicals Conflicts of interest: some authors received funding from the vaccine developer |
|
Rasmussen 2020‐DNK.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Denmark; 1997‐2018 V: individual vaccination status not used – pre‐/post‐introduction O: Danish Cancer Registry (national database) |
|
| Participants | N = not reported, females All ages | |
| Interventions | Not reported | |
| Outcomes | Vulvar cancer; VIN Follow‐up: 4 years |
|
| Notes | Source of funding: not reported Conflicts of interest: some authors received funding from the vaccine developer |
|
Rebolj 2022‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom; 2013‐2018 V: individual vaccination status not used – pre‐/post‐introduction O: National Health Service Cervical Screening Programme (national database) |
|
| Participants | N = 64,274 females 24 to 25 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Cervical cancer; CIN3+; CIN2+ Follow‐up: 7 years |
|
| Notes | Funding: Public Health England Conflicts of interest: none |
|
Restivo 2023‐ITA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Italy; 2008‐2018 V: individual vaccination status not used – pre‐/post‐introduction O: Italian hospital discharge records database |
|
| Participants | N = 483,373 females and males Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent), Gardasil 9 (Merck nonavalent) | |
| Outcomes | Cervical cancer, anal cancer, head and neck cancer, penile cancer, vulvar cancer, anogenital warts Follow‐up: cross‐sectional (repeated) |
|
| Notes | Funding: none Conflict of interest: none |
|
Reyburn 2023‐FJI.
| Study characteristics | ||
| Methods | Retrospective cohort study Fiji; October 2015 to March 2019 V: HPV immunisation register O: vaginal swab as part of antenatal testing |
|
| Participants | N = 835 pregnant women 15 to 23 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection; anogenital warts Follow‐up: 6 to 11 years |
|
| Notes | Source of funding: Bill & Melinda Gates Foundation and the Department of Foreign Affairs and Trade of the Australian Government and Fiji Health Sector Support Program (FHSSP) Conflicts of interest: some authors received funding from the vaccine developer |
|
Rodriguez 2020‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; January 2006‐December 2016 V: Optum’s Clinformatics DataMart Database (insurance database) O: Optum’s Clinformatics DataMart Database (insurance database) |
|
| Participants | N = 133,082 females Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN2+ Follow‐up: 22 years |
|
| Notes | Source of funding: public/non‐profit: National Institutes of Health; Cancer Prevention Research Institute of Texas Conflicts of interest: some authors received funding from the vaccine developer |
|
Rosenblum 2021‐USA.
| Study characteristics | ||
| Methods | Cohort study; pre‐ vs post‐vaccine introduction USA; 2003‐2018 V: self‐report O: self‐collected cervicovaginal specimens (NHANES) |
|
| Participants | N = not reported, females 14 to 69 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, repeated over 16 years |
|
| Notes | Source of funding: public/non‐profit: NIH, Cancer Prevention and Research Institute of Texas Conflicts of interest: no |
|
Ruiz‐Sternberg 2014‐COL.
| Study characteristics | ||
| Methods | Cohort study Colombia; May 2011‐March 2012 V: self‐administered survey O: self‐administered survey |
|
| Participants | N = 1436 females < 26 years |
|
| Interventions | Not reported | |
| Outcomes | Participation rates in screening Follow‐up: cross‐sectional |
|
| Notes | Source of funding: private/industry: Merck Conflicts of interest: no |
|
Sadler 2015‐GBR.
| Study characteristics | ||
| Methods | Cohort study; cross‐sectional United Kingdom (UK); September 2010‐October 2011 V: standardised clinical history form administered on successive consenting attendees by clinicians at genitourinary medicine clinics (study‐level targeted ascertainment) O: standardised clinical history form administered on successive consenting attendees by clinicians at genitourinary medicine clinics (study‐level targeted ascertainment) |
|
| Participants | N = 363 females 14 to 20 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Sexual activity (incidence of sexually transmitted infections); anogenital warts Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Medical Research Council Studentship; Max Elstein Trust ; Central Manchester University Hospitals NHS Foundation Trust Conflicts of interest: no |
|
Saeki 2024‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study; pre‐ vs post‐vaccine introduction Japan; April 2021‐November 2022 V: self‐report O: outpatient clinics with HPV screening |
|
| Participants | N = 1529 females 16 to 39 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Funding: research grant from vaccine manufacturer Conflicts of interest: none |
|
Saldanha 2020‐PRT.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Portugal; January 2010‐December 2019 V: not reported. Defined by birth cohorts. O: HPV test outcomes at a single laboratory |
|
| Participants | N = 1852 females < 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: not reported |
|
| Notes | Funding: no specific funding Conflicts of interest: authors have received speaker fees from a vaccine developer |
|
Sando 2014‐DNK.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Denmark; 2001‐2011 V: no individual vaccination status O: Register of Medical Products Statistics combined with data from the National Patient Register (national database) |
|
| Participants | N = not reported, females and males 15 to 34 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 2 years |
|
| Notes | Source of funding: not reported Conflicts of interest: some authors received funding from the vaccine developer |
|
Sankaranarayanan 2018‐IND.
| Study characteristics | ||
| Methods | RCT extension India; September 2009‐June 2019 V: RCT records O: cervical samples (study‐level targeted ascertainment) |
|
| Participants | N = 21,258 females (trial participants, community controls) 20 to 28 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer; CIN2+; incident HPV infection; persistent HPV infection Follow‐up: 5 years |
|
| Notes | Source of funding: mixed: public/non‐profit and private/industry: Bill & Melinda Gates Foundation; Merck Conflicts of interest: some authors received funding from the vaccine developer |
|
Sarr 2019‐CAN.
| Study characteristics | ||
| Methods | Cross‐sectional study Canada; 2010‐2016 V: self‐report O: self‐collected cervicovaginal specimen, using a dry polyester swab |
|
| Participants | N = 1035 females ≥ 18 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Canadian Institutes of Health Research (CHIR) Conflicts of interest: some authors received funding from the vaccine developer |
|
Sauvageau 2021‐CAN.
| Study characteristics | ||
| Methods | Cross‐sectional study Canada; 2013‐2014 V: computer‐assisted questionnaire (self‐report) (study‐level targeted ascertainment) O: computer‐assisted questionnaire (self‐report) (study‐level targeted ascertainment) |
|
| Participants | N = 1475 females 17 to 29 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Sexual activity (incidence of sexually transmitted infections); participation rates in screening Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Ministére de la Sante et des Services Sociaux du Quebec Conflicts of interest: some authors received funding from the vaccine developer |
|
Sayinzoga 2023‐RWA.
| Study characteristics | ||
| Methods | Cross‐sectional study Rwanda; July 2013‐December 2020 V: self‐report survey O: cervical cell samples for the detection of HPV DNA |
|
| Participants | N = 3140 females 17 to 29 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, repeated |
|
| Notes | Source of Funding: Bill & Melinda Gates Foundation Conflicts of interest: none |
|
Scheller 2017‐DNK.
| Study characteristics | ||
| Methods | Cohort study Denmark; October 2006‐November 2013 V: Childhood Vaccination database at Statens Serum Institut; The National Prescription Register (national database) O: The Medical Birth Register; The National Patient Register (national database) |
|
| Participants | N = not reported, females 12 to 27 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Birth outcomes Follow‐up: 7 years |
|
| Notes | Source of funding: public/non‐profit: Novo Nordisk Foundation; Danish Medical Research Council Conflicts of interest: no |
|
Schlecht 2016‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; study dates not reported V: medical records O: specimen collection was performed at each 6‐month visit by clinicians |
|
| Participants | N = 1139 females Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: median = 28.5 months ; mean = 30.9 (± 23.1) |
|
| Notes | Source of funding: public/non‐profit: National Institute of Allergy and Infectious Diseases; Icahn School of Medicine at Mount Sinai; National Cancer Institute Conflicts of interest: some authors received funding from the vaccine developer |
|
Schlecht 2019‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; October 2007‐April 2017 V: medical records O: oral rinse sample |
|
| Participants | N = 1259 females 13 to 21 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: National Institute of Allergy and Infectious Diseases; National Cancer Institute; Icahn School of Medicine at Mount Sinai Conflicts of interest: some authors received funding from the vaccine developer |
|
Schmuhl 2020‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study United States of America (USA); 2006‐2016 V: self report: National Health and Nutrition Examination Survey (NHANES) (study‐level targeted ascertainment) O: self report: National Health and Nutrition Examination Survey (NHANES) (study‐level targeted ascertainment) |
|
| Participants | N = 1114 females 18 to 33 years |
|
| Interventions | Not reported | |
| Outcomes | Infertility Follow‐up: 10 years |
|
| Notes | Source of funding: public/non‐profit: University of Wisconsin Carbone Cancer Center Conflicts of interest: not reported |
|
Schurink‐Van't Klooster 2018‐NLD.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Netherlands; January 2007‐December 2014 V: electronic national immunisation register 'Præventis’ (national database) O: electronic records (study‐level targeted ascertainment) |
|
| Participants | N = 69,429 females 12 to 16 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) Follow‐up: 5 years |
|
| Notes | Source of funding: public/non‐profit: Dutch Ministry of Health, ZONMW Conflicts of interest: no |
|
Schurink‐Van't Klooster 2023‐NLD.
| Study characteristics | ||
| Methods | Retrospective cohort study/database linkage Netherlands; January 2009‐March 2018 V: national vaccination registry (Praeventis) O: Dutch National Pathology Databank (PALGA) |
|
| Participants | N = 42,171 females 13 to 22 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | CIN3+ Follow‐up: up to 10 years |
|
| Notes | Funding: Ministry of Health, Welfare, and Sport, The Netherlands Conflicts of interest: none |
|
Shiko 2020‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; April 2015‐March 2017 V: questionnaire (self‐report) O: Japan Cancer Society cervical screening database (national database) |
|
| Participants | N = 34,281 females (attending cervical screening) 20 to 29 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | CIN3+; CIN2+ Follow‐up: 10 years |
|
| Notes | Source of funding: public/non‐profit: Research Programme on Emerging and Re‐emerging Infectious Diseases from Japan Agency for Medical Research and Development Conflicts of interest: some authors received funding from the vaccine developer |
|
Shilling 2021‐AUS.
| Study characteristics | ||
| Methods | Cohort study Australia; January 2015‐November 2018 V: National HPV Vaccination Program Register O: HPV DNA detection and genotyping |
|
| Participants | N = 1635 females 18 to 35 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, up to 8 years since vaccination |
|
| Notes | Source of funding: public/non‐profit: Commonwealth Department of Health HPV Surveillance Fund Conflicts of interest: some authors received funding from the vaccine developer |
|
Shing 2019‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; January 2006‐December 2014 V: no individual vaccination status O: TennCare, Tennessee's Medicaid program (insurance database) |
|
| Participants | N = 799,122 females and males 15 to 39 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional, repeated analyses |
|
| Notes | Source of funding: public/non‐profit: Centers for Disease Control and Prevention; National Center for Advancing Translational Sciences, National Institutes of Health Conflicts of interest: no |
|
Silverberg 2018‐USA.
| Study characteristics | ||
| Methods | Case‐control study USA; 2006‐2014 V: Kaiser Permanente Northern California electronic health record O: Kaiser Permanente Northern California electronic health record |
|
| Participants | N = 26,130 females Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN2+ Follow‐up not reported |
|
| Notes | Source of funding: public/non‐profit: National Cancer Institute at the National Institutes of Health Conflicts of interest: no |
|
Skufca 2018‐FIN.
| Study characteristics | ||
| Methods | Cohort study Finland; November 2013‐December 2016 V: Finnish National Vaccination Register (national database) O: national hospital discharge register (national database) |
|
| Participants | N = 240,605 females 11 to 15 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Postural orthostatic tachycardia syndrome (POTS); chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME); paralysis; complex regional pain syndrome (CRPS); Guillain‐Barré syndrome (GBS) Follow‐up: 3 years |
|
| Notes | Source of funding: not reported Conflicts of interest: authors are employed by the National Institute for Health and Welfare, which has received research funding from GlaxoSmithKline and Pfizer, Inc. |
|
Smith 2015‐CAN.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Canada; 2005‐2009 V: Immunization Records Information System (IRIS) (regional database) O: "Registered Persons’ Database; Ontario Health; Insurance Plan; Discharge Abstract Database; Same‐Day Surgeries; National Ambulatory Care Reporting System" (routine administrative database, national) |
|
| Participants | N = 260,493 females 13 to 17 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Sexual activity (incidence of sexually transmitted infections) Follow‐up: 4 years |
|
| Notes | Source of funding: public/non‐profit: Canadian Institutes of Health Research; Institute for Clinical Evaluative Sciences Conflicts of interest: no |
|
Smith 2016‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; 1 July 1999 and 30 June 2011 V: no individual vaccination status O: National Hospital Morbidity Database (NHMD) (national database) |
|
| Participants | N = 39,350 females and males 12 to 69 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: up to 5 years |
|
| Notes | Source of funding: public/non‐profit: National Health and Medical Research Council Australia; The National Centre for Immunisation Research; Australian Government Department of Health, the NSW Ministry of Health, the Children’s Hospital at Westmead Conflicts of interest: no |
|
Soderlund‐Strand 2014‐SWE.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Sweden; March 2008‐March 2013 V: individual vaccination status not used O: chlamydia screening |
|
| Participants | N = 55,185 females and males All ages |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: 3 repeated cross‐sectional surveys, over 6 years |
|
| Notes | Source of funding: public/non‐profit: Public Health Agency of Sweden Conflicts of interest: some authors received funding from the vaccine developer |
|
Sonnenberg 2019‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom (UK); 1999‐2012 V: no individual vaccination status O: self‐reported GW diagnosis |
|
| Participants | N = 18,963 females and males 16 to 44 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Medical Research Council; Wellcome trust; Economic and Social Research Council; Department of Health Conflicts of interest: no |
|
Spinner 2019‐USA.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction USA; 2006‐2017 V: Ohio statewide immunisation registry; electronic health record; self‐report O: cervicovaginal swabs (self‐swab or clinician swab) |
|
| Participants | N = 1580 females 13 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, repeated over 12 years |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: National Institutes of Health; Merck provided vaccine and serology testing Conflicts of interest: authors include stockholders of the vaccine developer |
|
Steben 2018‐CAN.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Canada; 2004‐2012 V: school public HPV vaccination programme with the quadrivalent vaccine Gardasil O: the provincial administrative databases of the Régie de l'Assurance Maladie du Québec (RAMQ): the physician service claims (PSCs) and the public drug plan insurance databases (insurance databases) |
|
| Participants | N = 21,411 females and males 15 to ≥ 30 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: not reported |
|
| Notes | Source of funding: not reported Conflicts of interest: authors include employees of the vaccine developer |
|
Subasinghe 2020‐AUS.
| Study characteristics | ||
| Methods | Cross‐sectional study Australia; 2021‐2017 V: National HPV Vaccination Program Register (NHVPR) O: self‐collected vaginal swab for the detection of HPV DNA |
|
| Participants | N = 344 females 16 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, follow‐up potentially to 10 years |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: National Health and Medical Research Council; Merck Sharp & Dohme Conflicts of interest: some authors received funding from the vaccine developer |
|
Swedish 2013‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; April 2007‐January 2013 V: medical records (hospital database) O: medical records (hospital database) |
|
| Participants | N = 313 males (MSM) 26 to 76 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: up to 4 years |
|
| Notes | Funding: no specific funding Conflicts of interest: some authors received funding from the vaccine developer |
|
Tabrizi 2014‐AUS.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Australia; October 2005‐November 2012 V: National HPV Vaccination Program Register O: exfoliated cervical cells collected for cervical cytology; self‐completed questionnaire |
|
| Participants | N = 1260 females 18 to 24 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, potential maximum 7 years after vaccination |
|
| Notes | Source of funding: public/non‐profit: Australian National Health and Medical Research Council and Cancer Council Victoria Conflicts of interest: authors include stockholders of the vaccine developer |
|
Tanaka 2017‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; January 2014‐October 2016 V: interviews (self‐report) O: cervical cytology/histology (study‐level targeted ascertainment) |
|
| Participants | N = 2425 females (attending cervical screening) 20 to 24 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | CIN2+ Follow‐up: cross‐sectional |
|
| Notes | Source of funding: not reported Conflicts of interest: no |
|
Taniguchi 2019‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; 2015 V: HPV vaccination status was confirmed from public records in the present study: HPV vaccination status was confirmed from public records in the present study O: survey – no other details |
|
| Participants | N = 2727 females 20 to 21 years |
|
| Interventions | Not reported | |
| Outcomes | Participation rates in screening Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Health and Labor Sciences Research Grant Conflicts of interest: some authors received funding from the vaccine developer |
|
Tanton 2017‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom (UK); 1999‐2012 V: self‐report O: urine samples |
|
| Participants | N = 471 females 18 to 20 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Medical Research Council; Wellcome Trust; Economic, Social Research Council and Department of Health Conflicts of interest: no |
|
Ter‐Minasyan 2024‐ARM.
| Study characteristics | ||
| Methods | Retrospective cohort study Armenia; dates not reported V: Armenian‐American Wellness Center O: Armenian‐American Wellness Center |
|
| Participants | N = 98 females 15 to 40 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Premature ovarian failure Follow‐up: not reported |
|
| Notes | Funding: not reported Conflict of interest: not reported |
|
Thamsborg 2020‐DNK.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Denmark; January 1999‐December 2018 V: pre‐/post‐vaccination introduction. No individual vaccination status used O: The National Register of Pathology (national database) |
|
| Participants | N = 45,844 females 15 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Participation rates in screening; CIN3+; CIN2+; CIN2 Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Independent Research Fund Denmark; Danish Health Foundation Conflicts of interest: no |
|
Thompson 2016‐CAN.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Canada; 1990‐2011 V: individual vaccination status not reported O: Manitoba’s administrative databases of Physician Claims and Hospital Discharge Abstracts |
|
| Participants | N = not reported, females and males All ages |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: cross‐sectional, repeated over 22 years |
|
| Notes | Funding: no specific funding Conflicts of interest: no |
|
Thomsen 2020‐DNK.
| Study characteristics | ||
| Methods | Cohort study, pre‐ vs post‐vaccine introduction, self‐controlled case series Denmark; January 2008‐December 2014 V: Danish National Health Service Register; Danish National Prescription Registry (national database) O: Danish National Patient Registry and Psychiatric Central Research Register (national database) |
|
| Participants | N = 628,034 females 11 to 17 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Postural orthostatic tachycardia syndrome (POTS); chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME); all‐cause mortality Follow‐up: 1 year |
|
| Notes | Source of funding: public/non‐profit: Danish Medicines Agency Conflicts of interest: no |
|
Thöne 2017‐DEU.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction Germany; 2005‐2010 V: no individual vaccine status data O: German Pharmacoepidemiological Research Database (insurance database) |
|
| Participants | N > 9,000,000 females and males (29,740,000 person‐years) 10 to 79 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 1 year |
|
| Notes | Source of funding: private/industry: Sanofi Pasteur MSD Conflicts of interest: some authors received funding from the vaccine developer |
|
Tozawa‐Ono 2021‐JPN.
| Study characteristics | ||
| Methods | Cross‐sectional study Japan; January 2015‐December 2016 V: questionnaire (self‐report) O: cervical cytology and histology (hospital database) |
|
| Participants | N = 11,903 females (attending cervical screening) 20 to 25 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN3; CIN2+; CIN2 Follow‐up: 10 years |
|
| Notes | Source of funding: not reported Conflicts of interest: no |
|
Tsai 2023‐TWN.
| Study characteristics | ||
| Methods | Retrospective cohort study/database linkage Taiwan; 2013‐2018 V: Taiwan’s National Immunization Information System O: Taiwan’s National Health Insurance Database |
|
| Participants | N = 227,393 vaccinated females 12 to 15 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent); Gardasil 9 (Merck nonavalent) | |
| Outcomes | Primary ovarian failure; chronic fatigue syndrome; Guillain‐Barré syndrome; complex regional pain syndrome Follow‐up: not reported |
|
| Notes | Funding: Health Promotion Administration (HPA), Ministry of Health and Welfare Conflicts of interest: none |
|
Van Eer 2021‐NLD.
| Study characteristics | ||
| Methods | Cross‐sectional study Netherlands; 2009‐2017 V: self‐report O: vaginal and anal swabs (self‐collected) |
|
| Participants | N = 542 females Age not reported |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Ministry of Health, Welfare and Sports, the Netherlands Conflicts of interest: no |
|
Verdoodt 2020‐DNK.
| Study characteristics | ||
| Methods | Cohort study Denmark; 2006‐2016 V: National Health Service Registry (national database) O: Danish national screening programme for cervical cancer (national database) |
|
| Participants | N = 590,083 females 17 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN2+ Follow‐up: cross‐sectional, longest potential follow‐up, 6 years |
|
| Notes | Source of funding: public/non‐profit: Mermaid Project and the Danish Council for Independent Research (Danmarks Frie Forskningsfond Sapere Aude‐program Conflicts of interest: some authors received funding from the vaccine developer |
|
Vielot 2020‐USA.
| Study characteristics | ||
| Methods | Cohort study United States of America (USA); June 2006‐December 2014 V: IBM MarketScan Commercial Database (national database) O: IBM MarketScan Commercial Database (national database) |
|
| Participants | N = 123,981 females 11 to 19 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Complex regional pain syndrome (CRPS) Follow‐up: 8 years |
|
| Notes | Source of funding: public/non‐profit: National Institute of Allergy and Infectious Diseases Conflicts of interest: no |
|
Ward 2024‐GBR.
| Study characteristics | ||
| Methods | Retrospective cohort study/regression discontinuity design United Kingdom; 2009‐2022 V: no individual vaccination status used; birth cohorts O: Hospital Episode Statistics |
|
| Participants | N = 1,445,512 females 17 to 22 years |
|
| Interventions | Cervarix (GSK bivalent); Gardasil (Merck quadrivalent) | |
| Outcomes | Cervical cancer | |
| Notes | Funding: not reported Conflicts of interest: not reported |
|
Wendland 2021‐BRA.
| Study characteristics | ||
| Methods | Cross‐sectional study Brazil; September 2016 to November 2017 V: vaccination status was self‐reported and was independent of the number of doses and intervals O: cervical samples were obtained using a Qiagen HC2 DNA collection device according to the manufacturer’s instructions. |
|
| Participants | N = 5945 females 16 to 25 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Hospital Moinhos de Vento through the Program for Supporting the Institutional Development of the Public Health System (PROADI‐SUS), supported by the Ministry of Health of Brazil Conflicts of interest: authors include employees of the vaccine developer |
|
Widdice 2019‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; 2013‐2017 V: self‐report, verified by medical records or vaccine registry in 85% of participants O: swab samples of the glans penis, including coronal sulcus; penile shaft; scrotum; and the perianal/anal area |
|
| Participants | N = 747 males 13 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional, repeated 2013‐2014 and 2016‐2017 |
|
| Notes | Source of funding: public/non‐profit: NIAID; National Institutes of Health Conflicts of interest: some authors received funding from the vaccine developer |
|
Willame 2016‐GBR.
| Study characteristics | ||
| Methods | Cohort study United Kingdom (UK); September 2005‐August 2010 V: Clinical Practice Research Datalink (national database) O: Clinical Practice Research Datalink (national database) and/or Hospital Episode Statistics (HES) (national database and routine administrative database, hospital) |
|
| Participants | N = 259,876 females and males 9 to 25 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Guillain‐Barré syndrome (GBS) Follow‐up: 1 year |
|
| Notes | Source of funding: private/industry: GlaxoSmithKline Biologicals Conflicts of interest: authors include employees of the vaccine developer |
|
Willows 2018‐CAN.
| Study characteristics | ||
| Methods | Cohort study Canada; August 2001‐December 2017 V: The Manitoba Immunization Monitoring System (MIMS) (regional database) O: hospital, physician and prescription claim databases |
|
| Participants | N = 125,791 females ≥ 9 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: 16 years |
|
| Notes | Source of funding: private/industry: Merck Canada Inc. Conflicts of interest: some authors received funding from the vaccine developer |
|
Winer 2021‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; 2016‐2018 V: self‐report O: self‐collected penile swab specimen |
|
| Participants | N = 687 (penile), 1391 (oral/anal) males 18 to 26 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional |
|
| Notes | Source of funding: public/non‐profit: Centers for Disease Control and Prevention Conflicts of interest: no |
|
Wissing 2019‐CAN.
| Study characteristics | ||
| Methods | Cohort study Canada; May 2005‐February 2011 V: web‐based questionnaires O: during clinical visits, genital specimens were collected, either by self‐sampling (vaginal samples) or by a nurse (penile samples of male partners) |
|
| Participants | N = 502 females ≥ 18 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Incident HPV infection; persistent HPV infection; prevalent HPV infection Follow‐up: 2 years |
|
| Notes | Source of funding: both public/non‐profit and private/industry sources: Canadian Institutes of Health Research; U.S. National Institutes of Health; Merck‐Frosst Canada Ltd., and Merck & Co. Ltd; Reseau sida et maladies infectieuses (SIDA/MI) du Fonds de recherche du Quebec ‐ Sante (FRQS) Conflicts of interest: some authors received funding from the vaccine developer |
|
Woestenberg 2020‐NLD.
| Study characteristics | ||
| Methods | Cross‐sectional study Netherlands; 2011‐2017 V: self‐report O: anal swabs |
|
| Participants | N = 548 females 16 to 24 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Prevalent HPV infection Follow‐up: cross‐sectional. Up to 8 years. |
|
| Notes | Source of funding: public/non‐profit: Ministry of Health, Welfare and Sport, the Netherlands Conflicts of interest: no |
|
Woestenberg 2021‐NLD.
| Study characteristics | ||
| Methods | Cohort study Netherlands; January 2007‐December 2015 V: national immunisation registry (Præventis) (national database) O: Nivel Primary Care Database (Nivel‐PCD) (national database) |
|
| Participants | N = 96,468 females (primary health care) Age not reported |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Anogenital warts Follow‐up: median 3 years |
|
| Notes | Source of funding: public/non‐profit: Netherlands Ministry of Health, Welfare and Sport Conflicts of interest: unclear |
|
Wright 2019‐USA.
| Study characteristics | ||
| Methods | Cross‐sectional study USA; August 2013‐June 2015 V: self‐report O: HPV testing, standardised colposcopy and biopsy protocols (study‐level targeted ascertainment) |
|
| Participants | N = 14,153 females (attending cervical screening) 21 to 34 years |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN2+; prevalent HPV infection Follow‐up: 10 years |
|
| Notes | Source of funding: private/industry: Becton, Dickinson and Company, BD Life Sciences Conflicts of interest: some authors received funding from the vaccine developer |
|
Xu 2021‐GBR.
| Study characteristics | ||
| Methods | Pre‐ vs post‐vaccine introduction United Kingdom (UK); 2006‐2016 V: no individual vaccination status O: Aberdeen Maternity and Neonatal Databank (routine administrative database, hospital) |
|
| Participants | N = not reported, females 20 to 30 years |
|
| Interventions | Cervarix (GSK bivalent) | |
| Outcomes | Birth outcomes Follow‐up: not reported |
|
| Notes | Source of funding: public/non‐profit: Newton visiting PhD fellowship Conflicts of interest: some authors received funding from the vaccine developer |
|
Yagi 2019‐JPN.
| Study characteristics | ||
| Methods | Cohort study Japan; 2011‐2016 V: no individual vaccine status data: pre‐/post‐eligibility birth cohorts O: cervical screening data (hospital database) |
|
| Participants | N = 15,261 females (attending cervical screening) 20 to 21 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | CIN3+; CIN3; CIN2+; CIN2; participation rates in screening Follow‐up: cross‐sectional |
|
| Notes | Source of funding:public/non‐profit: Health and Labor Sciences Research Grant Conflicts of interest: some authors received funding from the vaccine developer |
|
Yoon 2021‐KOR.
| Study characteristics | ||
| Methods | Cohort study; self‐controlled case series South Korea; January 2017‐December 2019 V: Korea Immunization Registry Information System (national database) O: National Health Information Database (national database) |
|
| Participants | N = 441,399 females 11 to 14 years |
|
| Interventions | Cervarix (GSK bivalent), Gardasil (Merck quadrivalent) | |
| Outcomes | Paralysis; Guillain‐Barré syndrome (GBS) Follow‐up: 3 years |
|
| Notes | Source of funding: public/non‐profit: Government‐wide R&D Fund project for infectious disease research (GFID), Republic of Korea Conflicts of interest: no |
|
Zeybek 2018‐USA.
| Study characteristics | ||
| Methods | Cohort study USA; 2006‐2015 V: Clinformatics Data Mart (CDM) Database (insurance database) O: Clinformatics Data Mart (CDM) Database (insurance database) |
|
| Participants | N = 573,926 females and males Age not reported |
|
| Interventions | Gardasil (Merck quadrivalent) | |
| Outcomes | Anogenital warts Follow‐up: up to 5 years |
|
| Notes | Source of funding: public/non‐profit: William & Mary McGanity Research Fund Award from the Department of Obstetrics & Gynecology at The University of Texas Medical Branch at Galveston Conflicts of interest: no |
|
O: source of outcome data; V: source of vaccination data
Other abbreviations: AGW: anogenital warts; AIN: anal intraepithelial neoplasia; CFS/ME: chronic fatigue syndrome/myalgic encephalomyelitis; CIN: cervical intraepithelial neoplasia; CIN2: cervical intraepithelial neoplasia grade 2; CIN2+: cervical intraepithelial neoplasia grade 2 or higher; CIN3: cervical intraepithelial neoplasia grade 3; CIN3+: cervical intraepithelial neoplasia grade 3 or higher; CRPS: complex regional pain syndrome; EMR: electronic medical record; GP: general practitioner; GUM: genitourinary medicine; GW: genital warts; HPV: human papillomavirus; ICD‐9/ICD‐10: International Statistical Classification of Diseases and Related Health Problems (9th/10th Revision); IQR: interquartile range; MSM: men who have sex with men; MSW: men who have sex with women; NR: not reported; POTS: postural orthostatic tachycardia syndrome; RCT: randomised controlled trial; SD: standard deviation; STD: sexually transmitted disease; STI: sexually transmitted infection; VaIN: vaginal intraepithelial neoplasia; VIN: vulval intraepithelial neoplasia; WSM: women who have sex with men; yo: year‐old
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Abbas 2023a | No relevant comparison |
| Abbas 2023b | No relevant comparison |
| Ai Sahlgren 2015 | Irrelevant population – already attending screening with positive result |
| Amend 2022 | No relevant comparison |
| An 2024 | No relevant comparison |
| Ansstasiou‐Fotaki 2007 | Study design not relevant |
| Aujo 2014 | No relevant outcome measures |
| Bailoni 2024 | No relevant population |
| Barry 2024 | Study design not relevant |
| Bayes 2011 | No relevant comparison |
| Bhardwaj 2022 | No relevant population |
| Bhatla 2023 | No relevant outcome measures |
| Block 2009 | Study design not relevant |
| Boudova 2023 | No relevant comparison |
| Brogly 2014 | No relevant outcome measures |
| Brouwer 2019 | No relevant outcome measures |
| Brouwer 2022a | No relevant outcome measures |
| Brouwer 2022b | No relevant outcome measures |
| Caskey 2022 | Study design not relevant |
| Castillo 2019 | No relevant outcome measures |
| Castillo‐Cano 2022 | No relevant outcome measures |
| Chambers 2023 | No relevant outcome measures |
| Chao 2012 | No relevant comparison |
| Chaopotong 2024 | No relevant outcome measures |
| Chen 2022 | No relevant comparison |
| Chidambaram 2023 | No relevant outcome measures |
| Chou 2022 | No relevant outcome measures |
| Cocores 2023 | No relevant comparison |
| Craig 2023 | No relevant comparison |
| Crawley 2022 | No relevant outcome measures |
| Dalla 2024 | No relevant comparison |
| Davis 2024 | No relevant outcome measures |
| Dehlendorff 2021 | No relevant outcome measures |
| Dey 2022 | No relevant comparison |
| Di Lorenzo 2022 | No relevant comparison |
| Donahue 2019 | No relevant comparison |
| Donken 2018 | No relevant outcome measures |
| Ehret 2023 | No relevant population |
| Eun 2023 | No relevant comparison |
| Fan 2023 | Study design not relevant |
| Fappani 2021 | No relevant population |
| Fatima 2022 | No relevant outcome measures |
| Fernandez‐Feito 2018 | No relevant outcome measures |
| Fisher 2023 | No relevant outcome measures |
| Forster 2012 | No relevant outcome measures |
| Freire‐Salinas 2021 | No relevant data available for extraction – unable to determine denominators |
| Frio 2021 | No relevant outcome measures |
| Garces 2022 | Study design not relevant |
| Gardella 2023 | Irrelevant population (all with CIN) |
| Garland 2022 | No relevant outcome measures |
| Gee 2011 | Study design not relevant – denominators are total adverse events |
| Geier 2015 | Study design not relevant – denominators are total adverse events |
| Geier 2017 | Study design not relevant – denominators are total adverse events |
| Gholamzad 2024 | No relevant outcome measures |
| Gibson 2022 | No relevant outcome measures |
| Grimaldi‐Bensouda 2023 | No relevant outcome measures |
| Groom 2023 | No relevant outcome measures |
| Grun 2015 | No relevant outcome measures |
| Grun 2016 | No relevant outcome measures |
| Guido 2020 | No relevant outcome measures |
| Guiqian 2020 | No relevant outcome measures |
| Guo 2022 | No relevant outcome measures |
| Hallam 2020 | Irrelevant population – already attending screening with positive result |
| Han 2017 | No relevant outcome measures |
| Hansen 2014 | No relevant outcome measures |
| Hansen 2023 | No relevant comparison |
| Hariri 2015a | Irrelevant population |
| Hariri 2015b | Irrelevant population – all with cervical disease |
| Hategeka 2020 | No relevant outcome measures |
| Hernandez‐Aguado 2022 | No relevant outcome measures |
| Hoes 2021 | No relevant comparison |
| Hofstetter 2016 | No relevant outcome measures |
| Holy 2024 | No relevant comparison |
| Iftner 2010 | No relevant outcome measures |
| Issanov 2022 | No relevant outcome measures |
| Jacobs 2024 | No relevant outcome measures |
| Johnson 2020 | Irrelevant population – all with high‐grade cervical lesions |
| Joshi 2023 | No relevant outcome measures |
| Karachentsova 2024 | Study design not relevant |
| Kenigsberg 2023 | No relevant comparison |
| Kerry‐Barnard 2021 | No relevant comparison |
| Klein 2024 | Study design not relevant |
| Krog 2024 | Irrelevant population (all CIN2) |
| Kwak 2024 | Study design not relevant |
| Lang 2023 | Study design not relevant |
| Lee K 2024 | No relevant comparison |
| Lee P 2024 | Study design not relevant |
| Lee S 2024 | No relevant outcome measures |
| Leidner 2020 | No relevant outcome measures |
| Liang 2022 | No relevant outcome measures |
| Liao 2022 | No relevant outcome measures |
| Lindquist 2024 | No relevant comparison |
| Loerinc 2023 | No relevant population |
| Lonky 2021 | Irrelevant population – already attending screening with positive result |
| Lopez‐Codony 2024 | No relevant population |
| Lynge 2024 | No relevant outcome measures |
| Magdaleno‐Tapial 2022 | No relevant comparison |
| Mahmud 2014 | No relevant outcome measures |
| Maldonado 2022 | No relevant comparison |
| Maldonado 2024 | No relevant outcome measures |
| Man 2023 | Study design not relevant (modelling) |
| Marchand 2013 | No relevant outcome measures |
| Matsumoto 2014 | No relevant outcome measures |
| Matsumoto 2017 | No relevant outcome measures |
| Matsumoto 2019 | No relevant outcome measures |
| Mattis 2023 | No relevant comparison |
| McClung 2019 | No relevant population |
| Megumi 2023 | No relevant comparison |
| Mehlsen 2022 | No relevant comparison |
| Meng 2023 | No relevant comparison |
| Mesher 2021 | No relevant outcome measures |
| Miranda 2024 | No relevant comparison |
| Mix 2021 | No relevant population |
| Mo 2024 | No relevant comparison |
| Morais 2024 | No relevant outcome measures |
| Munk 2024 | No relevant comparison |
| Murall 2020 | No relevant outcome measures |
| Murenzi 2023 | Study design not relevant |
| Na 2024 | No relevant population |
| Nakalembe 2014 | No relevant outcome measures |
| Naleway 2023 | Study design not relevant |
| Nasreen 2023 | No relevant outcome measures |
| Niccolai 2017 | No relevant comparison |
| Ntanika 2023 | No relevant outcome measures |
| Ogilvie 2018 | No relevant outcome measures |
| Oh 2024 | No relevant outcome measures |
| Onuki 2022a | Irrelevant population (all with CIN) |
| Onuki 2022b | Irrelevant population (all with CIN) |
| Paavonen 2009 | Study design not relevant |
| Panwar 2022 | No relevant outcome measures |
| Passos 2022 | No relevant outcome measures |
| Pesut 2024 | No relevant comparison |
| Petry 2013 | No relevant outcome measures |
| Pimenoff 2023 | Study design not relevant |
| Powell 2012 | No relevant outcome measures |
| Qiu 2024 | No relevant outcome measures |
| Ramogola‐Masire 2022 | No relevant population |
| Ratanasiripong 2014 | No relevant outcome measures |
| Restrepo 2023 | No relevant comparison |
| Righolt 2019 | No relevant outcome measures |
| Rossotti 2024 | Irrelevant population (all vaccinated) |
| Rotert 2022 | Irrelevant population (unclear vaccination proportion) |
| Rourke 2024 | No relevant outcome measures |
| Sastre‐Canton 2019‐ESP | No relevant outcomes |
| Satanova 2024 | No relevant outcome measures |
| Seeger 2023 | No relevant outcome measures |
| Sehnal 2022 | Study design not relevant |
| Seoud 2022 | No relevant comparison |
| Serafini 2024 | No relevant outcome measures |
| Sheth 2024 | Study design not relevant |
| Shin 2022 | No relevant outcome measures |
| Shing 2024 | No relevant outcome measures |
| Sivars 2023 | Irrelevant population (all with SCC) |
| Sonnenberg 2013 | No relevant outcome measures |
| Stefanizzi 2023 | No relevant comparison |
| Sundaram 2022 | No relevant comparison |
| Svarrer 2019 | No relevant outcome measures |
| Tan 2023 | No relevant comparison |
| Tarrash 2023 | Study design not relevant |
| Tatang 2021 | No relevant outcome measures |
| Teoh 2022 | Irrelevant population (all with abnormal cytology) |
| Trenque 2022 | No relevant outcome measures |
| Tsang 2022 | No relevant outcome measures |
| Tsukamoto 2022 | Study design not relevant |
| Valle 2022 | No relevant comparison |
| Van Eer 2023 | No relevant outcome measures |
| Van Trang 2022 | No relevant outcome measures |
| Velentzis 2023 | Study design not relevant |
| Wang 2024 | No relevant outcome measures |
| Wei 2022 | No relevant outcome measures |
| Welby 2023 | Study design not relevant |
| Wu 2023 | No relevant comparison |
| Yagi 2024 | Study design not relevant (modelling) |
| Yasuda 2024 | Study design not relevant |
| Zhang 2023 | No relevant comparison |
| Zhang 2024 | No relevant comparison |
| Zhao 2023 | Irrelevant study design (RCT) |
| Zheng 2022 | No relevant comparison |
CIN: cervical intraepithelial neoplasia; CIN2: cervical intraepithelial neoplasia grade 2; RCT: randomised controlled trial; SCC: squamous cell carcinoma
Characteristics of studies awaiting classification [ordered by study ID]
De Kloe 2024.
| Methods | Retrospective cohort study |
| Participants | Patients 9 to 39 years old attending medical encounters |
| Interventions | HPV vaccination |
| Outcomes | Malignancies at the following sites: head and neck (HNC), cervix, anus and anal canal, penis, vulva and vagina |
| Notes | Conference abstract with insufficient details about population for inclusion. Awaiting full publication. |
Dominicci‐Maura 2024.
| Methods | Prospective cohort study |
| Participants | Women aged 21 to 50 attending gynaecology and colonoscopy clinics |
| Interventions | HPV vaccination |
| Outcomes | Any HPV, high‐risk HPV, low‐risk HPV and specific HPV types |
| Notes | Conference abstract with insufficient details about population for inclusion. Awaiting full publication. |
Elshourbagy 2022.
| Methods | Self‐controlled case series |
| Participants | Patients with Guillain‐Barré syndrome in Vaccine Adverse Event Reporting System |
| Interventions | HPV vaccination |
| Outcomes | Guillain‐Barré syndrome |
| Notes | Conference abstract with insufficient details about population for inclusion. Awaiting full publication. |
Lau 2023.
| Methods | Prospective cohort study |
| Participants | Patients evaluated for anal dysplasia by two colorectal surgeons |
| Interventions | HPV vaccination |
| Outcomes | Anal dysplasia rates |
| Notes | Conference abstract with insufficient detail in outcomes reported for inclusion. Awaiting full publication. |
Neerukonda 2023.
| Methods | Ecologic study |
| Participants | Females in Florida and New York |
| Interventions | HPV vaccination |
| Outcomes | Cervical cancer incidence and death |
| Notes | Conference abstract with insufficient details about population for inclusion. Awaiting full publication. |
HNC: head and neck cancer; HPV: human papillomavirus
Differences between protocol and review
We have included an additional secondary outcome, prevalent HPV infection, as this was omitted from the protocol. The review now includes incident HPV infection, prevalent HPV infection and persistent HPV infection as secondary outcomes.
We have removed outcomes about lesions associated with HPV types included in the vaccines to reduce the overall number of outcomes and focus the review on overall rates of lesions and cancers associated with HPV.
We planned to use all studies we identified as relevant as seeds in the Science Citation Index ISI Web of Knowledge ResearchGate and Google Scholar to determine whether articles citing these studies were also relevant. Based on the large number of studies already identified by the search, we considered this step to be an unnecessary amount of work for very little yield.
Analysis was also planned for unadjusted data, however these were considered at critical risk of bias and therefore we limited analysis to adjusted effect estimates.
We performed an additional subgroup analysis of adjusted estimates of effect in those receiving the HPV vaccine at age 16 or younger. RCTs of HPV vaccine have demonstrated better efficacy in younger age groups before the onset of sexual activity, and most community HPV vaccine programmes are designed for younger age groups. Catch‐up programmes in older girls are therefore likely to lead to an underestimate of effect, hence this additional analysis was included.
Contributions of authors
JM, GV, YKL, MK, SPG, KD, EJC HB and NH conceived and designed the review. NH, HB, BSB, HMM, KP and GV contributed to the acquisition and analysis of data. All authors contributed to the interpretation of data. NH drafted the review, with input from JM, which was reviewed by all authors.
Sources of support
Internal sources
-
Cochrane, UK
In‐kind support for statistical analysis
External sources
-
NIHR Evidence Synthesis Programme Grants Reference: NIHR133046, UK
National Institute for Health Research (NIHR) Evidence Synthesis Programme Grant to support the production of this population‐level review of longer‐term outcomes and a parallel network meta‐analysis of randomised controlled trials.
Declarations of interest
Nicholas Henschke: declared that they have no conflict of interest.
Hanna Bergman: declared that they have no conflict of interest.
Brian Buckley: declared that they have no conflict of interest.
Emma J Crosbie: is an NIHR Research Professor and Honorary Consultant Gynaecological Oncologist at the University of Manchester and Manchester University NHS Foundation Trust. EJC treats patients with HPV‐related conditions, including cervical and vulval cancer and pre‐cancer. EJC reports an NIHR grant to support performing this review (academic support to perform the review from a non‐conflicted source); paid to institution. EJC is Deputy Editor in Chief for BJOG; personal payment. EJC is President of Peaches Womb Cancer Trust; unpaid. EJC is Chair of the Research Advisory Committee for The Eve Appeal; unpaid. EJC has received honoraria from GlaxoSmithKline and Astellas; personal payment. EJC has received research grants from Roche and Novosanis; paid to institution.
Kerry Dwan: declared that they have no conflict of interest.
Su P Golder: declared that they have no conflict of interest.
Maria Kyrgiou: reports a NIHR EME grant to support the NOVEL trial (trial assessing value of vaccine in women having conisation for CIN). MSD is only providing the vaccine for this trial; the NIHR EM grant payment is to the institution. MK is an author of the article ‘Human papillomavirus vaccination: The ESGO‐EFC position paper of the European society of Gynaecologic Oncology and the European Federation for colposcopy’ (Joura EA, Kyrgiou M, Bosch FX, Kesic V, Niemenen P, Redman CW, Gultekin M. Eur J Cancer. 2019 Jul;116:21‐26. doi: 10.1016/j.ejca.2019.04.032. Epub 2019 Jun 1. PMID: 31163338). MK works as a consultant in the Imperial Healthcare NHS Trust.
Yoon Kong Loke: reports grant funding from the NIHR; payment to institution.
Heather M McIntosh: declared that they have no conflict of interest.
Katrin Probyn: declared that they have no conflict of interest.
Gemma Villanueva: declared that they have no conflict of interest.
Jo Morrison: reports a NIHR grant to support performing this review (academic support to perform the review from a non‐conflicted source); personal payment. JM is the Co‐Chair of the British Gynaecological Cancer Society (BGCS) guidelines subgroup; unpaid position. JM has published opinions on Twitter, and co‐wrote a Cochrane editorial about a previous HPV vaccine review. JM is a consultant gynaecologist in Somerset NHS Foundation Trust. JM treats patients with HPV‐related conditions, including cervical and vulval cancer and pre‐cancer. Clinical expertise is informed by the results of the studies included in the previous HPV vaccine reviews and JM is a member of the NHS Cervical Screening Research Advisory Committee (unpaid). JM was a Co‐ordinating Editor in Cochrane at the time of previous versions of HPV vaccine reviews. JM is a Senior Editor for Cochrane (Sexual and Reproductive Health Thematic Group), although the author was not involved in the editorial process for this review.
New
References
References to studies included in this review
Abel 2021‐USA {published data only}
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Ali 2013‐AUS {published data only}
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Baldur‐Felskov 2014‐DNK {published data only}
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Baldur‐Felskov 2015‐DNK {published data only}
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Baril 2015‐GBR {published data only}
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Carozzi 2018‐ITA {published data only}
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Castle 2019‐USA {published data only}
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Chambers 2022‐CAN {published data only}
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Clark 2021‐CAN {published data only}
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Cocchio 2017‐ITA {published data only}
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Combita 2021‐COL {published data only}
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Crowe 2014‐AUS {published data only}
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Cummings 2012‐USA {published data only}
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De Souza 2023‐AUS {published data only}
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Feiring 2017‐NOR {published data only}
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Wendland 2021‐BRA {published data only}
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References to studies excluded from this review
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References to studies awaiting assessment
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