Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors

Marc Arbyn; Lan Xu; Cindy Simoens; Pierre PL Martin‐Hirsch

doi:10.1002/14651858.CD009069.pub3

. 2018 May 9;2018(5):CD009069. doi: 10.1002/14651858.CD009069.pub3

Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors

Marc Arbyn ^1,^✉, Lan Xu ¹, Cindy Simoens ², Pierre PL Martin‐Hirsch ³

Editor: Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Group

PMCID: PMC6494566 PMID: 29740819

Abstract

Background

Persistent infection with high‐risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical precancer and cancer. HPV types 16 and 18 cause approximately 70% of cervical cancers worldwide.

Objectives

To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women.

Search methods

We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase (June 2017) for reports on effects from trials. We searched trial registries and company results' registers to identify unpublished data for mortality and serious adverse events.

Selection criteria

Randomised controlled trials comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine).

Data collection and analysis

We used Cochrane methodology and GRADE to rate the certainty of evidence for protection against cervical precancer (cervical intraepithelial neoplasia grade 2 and above [CIN2+], CIN grade 3 and above [CIN3+], and adenocarcinoma‐in‐situ [AIS]), and for harms. We distinguished between the effects of vaccines by participants' baseline HPV DNA status. The outcomes were precancer associated with vaccine HPV types and precancer irrespective of HPV type. Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets.

Main results

We included 26 trials (73,428 participants). Ten trials, with follow‐up of 1.3 to 8 years, addressed protection against CIN/AIS. Vaccine safety was evaluated over a period of 6 months to 7 years in 23 studies. Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes. All but one of the trials was funded by the vaccine manufacturers. We judged most included trials to be at low risk of bias. Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7). Most women were under 26 years of age. Three trials recruited women aged 25 and over. We summarize the effects of vaccines in participants who had at least one immunisation.

Efficacy endpoints by initial HPV DNA status

hrHPV negative

HPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo in adolescent girls and women aged 15 to 26. There is high‐certainty evidence that vaccines lower CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10). There is moderate‐certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82).

HPV vaccines reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty). The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines (bivalent: RR 0.08 (0.03 to 0.23), high certainty; quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty). Data in older women were not available for this comparison.

HPV16/18 negative

In those aged 15 to 26 years, vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty and RR 0.09 (0.01 to 0.72), moderate certainty, respectively). No trials in older women have measured these outcomes.

Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions.

Regardless of HPV DNA status

In younger women HPV vaccines reduce the risk of CIN2+ associated with HPV16/18 from 341 to 157/10,000 (RR 0.46 (0.37 to 0.57), high certainty). Similar reductions in risk were observed for CIN3+ associated with HPV16/18 (high certainty). The number of women with AIS associated with HPV16/18 is reduced from 14 to 5/10,000 with HPV vaccines (high certainty).

HPV vaccines reduce any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty). The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)).

In women vaccinated at 24 to 45 years of age, there is moderate‐certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS.

Adverse effects

The risk of serious adverse events is similar between control and HPV vaccines in women of all ages (669 versus 656/10,000, RR 0.98 (0.92 to 1.05), high certainty). Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 [0.85 to 1.98]; low certainty). The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established.

Pregnancy outcomes

Among those who became pregnant during the studies, we did not find an increased risk of miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty). The effects on congenital abnormalities and stillbirths are uncertain (RR 1.22 (0.88 to 1.69), moderate certainty and (RR 1.12 (0.68 to 1.83), moderate certainty, respectively).

Authors' conclusions

There is high‐certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate‐certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status.

We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long‐term of follow‐up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes.

Plain language summary

HPV vaccination to prevent cancer and pre‐cancerous changes of the cervix

Background  Human papillomaviruses (HPV) are sexually transmitted and are common in young people. Usually they are cleared by the immune system. However, when high‐risk (hr) types persist, they can cause the development of abnormal cervical cells, which are referred to as cervical precancer if at least two thirds of the surface layer of the cervix is affected. Precancer can develop into cervical cancer after several years. Not everyone who has cervical precancer goes on to develop cervical cancer, but predicting who will is difficult. There are a number of different hrHPV types which can cause cervical precancer and cancer. HPV16 and 18 are the most important high‐risk types, since they cause about 70% of cervical cancers worldwide. Preventive vaccination, by injection of HPV virus‐like particles in the muscle, triggers the production of antibodies which protect against future HPV infections.

Review question  Does HPV vaccination prevent the development of cervical precancer or cancer and what are the harms?

Main results  We included 26 studies involving 73,428 adolescent girls and women. All trials evaluated vaccine safety over a period 0.5 to 7 years and ten trials, with follow‐up 3.5 to 8 years, addressed protection against precancer. Cervical cancer outcomes are not available. Most participants enrolled were younger than 26 years of age. Three trials recruited women between 25 to 45 years. The studies compared HPV vaccine with a dummy vaccine.

We assessed protection against precancer in individuals who were free of hrHPV, free of HPV16/18 or those with or without HPV infection at the time of vaccination. We separately assessed precancer associated with HPV16/18 and any precancer.

Protection against cervical precancer

1) Women free of hrHPV

Outcomes were only measured in the younger age group for this comparison (15 to 25 years). HPV vaccines reduce the risk of cervical precancer associated with HPV16/18 from 164 to 2/10,000 women (high certainty). They reduce also any precancer from 287 to 106/10,000 (high certainty).

2) Women free of HPV16/18

The effect of HPV vaccines on risk of precancer differ by age group. In younger women, HPV vaccines reduce the risk of precancer associated with HPV16/18 from 113 to 6/10,000 women (high certainty). HPV vaccines lower the number of women with any precancer from 231 to 95/10,000 (high certainty). In women older than 25, the vaccines reduce the number with precancer associated with HPV16/18 from 45 to 14/10,000 (moderate certainty).

3) All women with or without HPV infection

In those vaccinated between 15 to 26 years of age, HPV vaccination reduces the risk of precancer associated with HPV16/18 from 341 to 157/10,000 (high certainty) and any precancer from 559 to 391/10,000 (high certainty).

In older women, vaccinated between 25 to 45 years of age, the effects of HPV vaccine on precancer are smaller, which may be due to previous exposure to HPV. The risk of precancer associated with HPV16/18 is probably reduced from 145/10,000 in unvaccinated women to 107/10,000 women following HPV vaccination (moderate certainty). The risk of any precancer is probably similar between unvaccinated and vaccinated women (343 versus 356/10,000, moderate certainty).

Adverse effects

The risk of serious adverse events is similar in HPV and control vaccines (placebo or vaccine against another infection than HPV (high certainty). The rate of death is similar overall (11/10,000 in control group, 14/10,000 in HPV vaccine group) (low certainty). The number of deaths overall is low although a higher number of deaths in older women was observed. No pattern in the cause or timing of death has been established.

Pregnancy outcomes

HPV vaccines did not increase the risk of miscarriage or termination of pregnancy. We do not have enough data to be certain about the risk of stillbirths and babies born with malformations (moderate certainty).

Conclusion  There is high‐certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and women who are vaccinated between 15 and 26 years of age. The protection is lower when a part of the population is already infected with HPV. Longer‐term follow‐up is needed to assess the impact on cervical cancer. The vaccines do not increase the risk of serious adverse events, miscarriage or pregnancy termination. There are limited data from trials on the effect of vaccines on deaths, stillbirth and babies born with malformations.

Summary of findings

Background

Description of the condition

Burden of cervical cancer

Cervical cancer is the fourth most common cancer in women worldwide. It is estimated that in 2012, approximately 528,000 women developed cervical cancer and that 266,000 died from the disease (Ferlay 2015). Eighty‐six per cent of cervical cancer cases occur in developing countries (Arbyn 2011). Cervical cancer is the predominant cancer in women in Eastern Africa, South‐Central Asia and Melanesia, where a woman's risk of developing this disease by age 75 years ranges between 2.3% and 3.9%. In many developed countries, the incidence of, and mortality from, squamous cervical cancer has dropped substantially over the last decades, as a consequence of population‐based screening programmes (Arbyn 2009; Bray 2005a; Ferlay 2015; IARC 2005). However, approximately 54,000 and 11,000 cases are reported each year in Europe and the USA, respectively (Arbyn 2011; Ferlay 2013), and screening with cytology is less effective at preventing cervical adenocarcinoma (Bray 2005; Smith 2000). In contrast to many other malignancies, cervical cancer primarily affects younger women, with the peak age of incidence in the UK now between 25 and 29 years; between 2012 and 2014, 52% of cancers occurred in those under 45 years of age (Cancer Research UK 2018). In the UK (2010 to 2011), despite a comprehensive screening programme, 37% of women with cervical cancer died from the disease within 10 years of diagnosis (Cancer Research UK 2018).

High‐grade cervical intraepithelial neoplasia (CIN2+) is treated by local destruction (ablation) or excision of neoplastic tissue (Jordan 2009). Therapeutic procedures are similarly effective (Martin‐Hirsch 2013), but are associated with an average risk of residual or recurrent CIN2+ of 7% (Arbyn 2017), and an increased risk of late miscarriage and premature labour (Kyrgiou 2017). Primary prevention of CIN lesions by prophylactic (an agent used to prevent disease) vaccination can therefore reduce the burden, costs and adverse effects associated with its treatment.

Association between human papillomavirus (HPV) infection and cervical cancer and other HPV‐related cancers and their precursors

Papillomaviruses are small, icosahedral DNA viruses, that consist of one single double‐stranded circular DNA molecule of approximately 8,000 base‐pairs, contained within a protein capsid. The capsid is composed of two structural proteins, both are encoded by the viral genome: L1 and L2 (IARC 2007). The natural history of HPV infection towards cervical precancer and finally invasive cancer is well documented (Bosch 2002; Castellsagué 2006; IARC 2007). The development of cervical cancer passes through a number of phases: (a) infection of the cervical epithelium with high‐risk human papillomaviruses (hrHPV); (b) persistence of the HPV infection; (c) progression to precancerous lesions with malignant transformation of infected cells; and (d) invasion of surrounding tissue. The steps prior to development of cancer, can regress spontaneously, although regression rates decrease with increasing severity of the precancerous lesion.

Twelve hrHPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) are causally linked with the development of cervical cancer (Bouvard 2009). HPV68 is considered as probably carcinogenic (Schiffman 2009). Some other HPV types may in rare occasions also cause cervical cancer (Arbyn 2014). HPV type 16, in particular, has a high potential for malignant transformation of infected cervical cells (Schiffman 2005). The HPV types 16 and 18 jointly cause seven out of 10 cervical cancers worldwide (Munoz 2004). The five next most important high‐risk HPV types (HPV31, HPV33, HPV45, HPV52, and HPV58) together with HPV16/18 are causally linked with approximately 90% of cervical cancers (de Sanjose 2010). HPV16 is also linked with rarer types of cancer, such as cancer of the vulva and vagina in women, penile cancer in men and anal and oropharyngeal cancer in women and men (Cogliano 2005; IARC 2007).

The low‐risk HPV types 6 and 11 cause approximately 90% of genital warts in women and men (Lacey 2006). They occur in low‐grade dysplastic cervical lesions, but are not associated with developing cervical cancer (IARC 2007). HPV types 6 and 11 cause recurrent respiratory papillomatosis, a rare but very serious disease of the upper airways often requiring repetitive surgical interventions (Lacey 2006).

The main route of HPV transmission is sexual contact. Infection usually occurs soon after the onset of sexual activity (Winer 2003; Winer 2008). The prevalence of HPV infection in women generally peaks in late teenage or early twenties (de Sanjose 2007). HPV infection is usually cleared by the immune system (Ho 1998). HPV infection can result in cervical precancer (cervical intraepithelial neoplasia (CIN)), which can be detected by cervical cytological screening. By microscopic inspection of a cervical smear (also known as a Papanicolaou or 'Pap' test, cervical lesions can be detected (atypical squamous cells of undetermined significance (ASC‐US), low‐grade squamous intraepithelial lesion (LSIL), high‐grade squamous intraepithelial lesion (HSIL),: atypical glandular cells (AGC); for a complete list of abbreviations used in the review, see Appendix 1), which can be confirmed histologically following a cervical biopsy at colposcopic examination (Jordan 2008). In some countries, cytological cervical cancer screening is being replaced by HPV‐based screening, because the latter is more effective at preventing future CIN3 or invasive cancer (Arbyn 2012; Ronco 2014).

A World Health Organization (WHO) expert group accepted a reduction in the incidence of high‐grade CIN (CIN2+) and cervical adenocarcinoma in situ (AIS) or worse as an acceptable surrogate outcome of HPV vaccination trials (Pagliusi 2004). This is because the reduction of the incidence of invasive cervical cancer would require large and very long‐term studies, which are unlikely to be undertaken. The progression of HPV infection to invasive cancer is thought to take a minimum of 10 years (IARC 2007). Although CIN can regress, from historical data, it has been estimated that CIN3 has a probability of progressing to invasive cancer of 12% to 30%, whereas for CIN2 this probability is substantially lower (McCredie 2008; Ostor 1993).

The recognition of the strong causal association between HPV infection and cervical cancer led to the development of molecular HPV assays to detect cervical cancer precursors (Iftner 2003), and of vaccines that prevent HPV infection (prophylactic vaccines) or that aim to treat present HPV infection or HPV‐induced lesions (therapeutic vaccines) (Frazer 2004; Galloway 2003; Schneider 2003). Therapeutic vaccines are still in early experimental phases and are not further considered in this review.

Throughout this review, we will use the 2001 Bethesda System to define cytologically‐defined neoplastic lesions of the cervical epithelium (Solomon 2002) and the CIN nomenclature to define histologically‐confirmed CIN (Richart 1973).

Description of the intervention

The intervention evaluated in this review is prophylactic vaccination against the most carcinogenic HPV types. Prophylactic HPV vaccines are composed of virus‐like particles (VLPs) of the L1 protein, which is the major protein of the capsid (shell) of the HPV virus. VLPs, do not contain viral DNA, and so are incapable of causing an active infection.

This review addresses evidence of three prophylactic HPV vaccines that have been clinically evaluated in randomised controlled trials (RCTs): a monovalent HPV16 vaccine (manufactured by Merck, Sharpe & Dome (Merck), Whitehouse Station, NJ, USA); a quadrivalent vaccine, containing the L1 protein of HPV6, HPV11, HPV16 and HPV18 (Gardasil®, produced by the same manufacturer as the monovalent vaccine); and a bivalent vaccine containing L1 of HPV types 16 and 18 (Cervarix®, produced by GlaxoSmithKline (GSK), Rixensart, Belgium). The vaccines produced by Merck contain amorphous aluminium hydroxyphosphate sulphate as an adjuvant, whereas the GSK vaccine contains aluminium salt and AS04 or monophosphoryl lipid A, which is an immunostimulating molecule (WHO 2009). Recently, a nona‐valent vaccine targeting nine HPV types (HPV types 6, 11, 16, 18, 31, 33, 35, 45, 52 and 58) has been developed by Merck. We did not include the nona‐valent vaccine in the current review, since the randomised trials assessing the efficacy of the nona‐valent vaccine did not incorporate an arm with a non‐HPV vaccine control, Nevertheless, data regarding the nona‐valent vaccine are included in the Discussion. More details about the prophylactic HPV vaccines used are described in Appendix 2.

How the intervention might work

Animal experiments have shown that neutralising antibodies, elicited by vaccination with papillomavirus VLPs, prevent type‐specific infection and subsequent development of lesions after viral challenge (Breitburd 1995; Ghim 2000; Stanley 2006). Vaccination by intramuscular injection of L1 VLPs in humans has been demonstrated to be highly immunogenic in phase I trials, which means that they induce high titres of anti‐HPV antibodies in serum which are considerably higher than after natural infection. (Ault 2004; Brown 2001; Evans 2001; Harro 2001). Serum anti‐L1 antibodies can transudate to the mucosa (cervical or other sites) where new HPV infection is impeded through virus‐neutralisation (Stanley 2012). Prophylactic HPV vaccines may also induce specific memory B‐lymphocytes which play a role in long‐term humoral immunity (Giannini 2006). Anti‐HPV antibodies do not trigger the elimination of an existing HPV infection. Cell‐mediated immunity is required for viral clearance and regression of CIN lesions (Stanley 2012).

Why it is important to do this review

Several phase II and III studies have been conducted to date and numerous reviews have tried to summarise the results (Ault 2007; Arbyn 2007; Harper 2009; Initiative 2009; Kahn 2009; Kjaer 2009; Koutsky 2006; Lu 2011; Medeiros 2009; Rambout 2007; Szarewski 2010). However, none of the reviews combined information on all the available endpoints. Our purpose was to pool efficacy outcomes only when outcomes were similarly defined, taking the timing of follow‐up into account. This review is also important since it provides a template for reporting future results of prophylactic vaccination trials according to the different outcomes (infections or cervical precancerous lesions, either associated with infection with vaccine types or irrespective of HPV infection) for different exposure groups (defined essentially by absence of hrHPV, absence of the HPV types included in the vaccine, or regardless of HPV infection at enrolment). Particular effort was undertaken to assess severe adverse effects in order to inform health professionals, stakeholders, adolescent girls and women, not only about the potential beneficial effects of HPV vaccines but also about possible harms.

Objectives

To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women.

Methods

Criteria for considering studies for this review

Types of studies

We considered only phase II and phase III randomised controlled trials (RCTs).

Types of participants

We included studies enrolling female participants, without any age restriction, distinguishing:

female participants with no evidence of baseline infection with high‐risk human papillomaviruses (hrHPV) types (this group reflects the first target of basic vaccination programmes, i.e. girls before onset of sexual activity);
female participants with no evidence of baseline infection with HPV types included in the vaccines (per protocol population);
all female participants regardless of baseline infection with HPV (this group reflects the target of catch‐up vaccination programs, adolescents or young adult women aged 15 to 26 years, where a considerable proportion may already have been exposed to HPV infection).

The distinction of different participant categories by HPV status at enrolment is essential, since the trial outcomes are expected to differ in women who are already infected with HPV types included in the vaccine and those who are not infected, Further distinction was made by:

broad age group (adolescents and young adult women, aged 15 to 26 years) and mid‐adult women (25 to 45 years);
number of received doses: three doses in agreement with the trial protocol, at least one dose, and fewer than three doses (the latter analysis being a post‐hoc assessment);
type of vaccine received (mono‐, bi‐ or quadrivalent vaccine).

Studies with male participants or special target groups such as immunocompromised patients were not included. However, trials enrolling both female and male participants were potentially eligible under the condition that separate outcomes for female participants were reported or could be obtained from the authors.

Types of interventions

Intervention

Vaccination with prophylactic HPV vaccines containing virus‐like particles composed of the L1 capsid protein of HPV16 (monovalent vaccine), HPV16 and HPV18 (bivalent vaccine), or HPV6, HPV11, HPV16 and HPV18 (quadrivalent vaccine) (see Appendix 2). All vaccines were administered by intramuscular injection over a period of six months. The monovalent and quadrivalent vaccines were injected at zero, two and six months, whereas the bivalent vaccine was administered at zero, one and six months.

Comparison

Administration of placebo containing no active product or only the adjuvant of the HPV vaccine, without L1 VLP, or another non‐HPV vaccine.

In head‐to‐head trials comparing directly the bivalent with the quadrivalent vaccine, participants who received the bivalent vaccine constituted the experimental group and participants who received the quadrivalent vaccine were considered as the comparison group.

Types of outcome measures

Primary outcomes

Histologically‐confirmed high‐grade cervical intraepithelial neoplasia (CIN2, CIN3 and adenocarcinoma in situ (AIS)) or worse, associated with the HPV types included in the vaccine or any lesions irrespective of HPV type. Association between HPV types and a diagnosed lesion means that the particular type or types have been detected in that lesion. These primary outcomes were judged by WHO to be adequate endpoints (Pagliusi 2004).
Invasive cervical cancer.
Safety/occurrence of adverse effects:

- 1. local adverse effects (redness, swelling, pain, itching at the injection site);
  2. mild systemic effects;
  3. serious systemic effects;
  4. mortality;
  5. pregnancy outcomes observed during the trials, in particular occurrence of congenital anomalies.

Secondary outcomes

Incident infection with vaccine HPV types (HPV16 and HPV18, jointly; and HPV6, HPV11, HPV16 and HPV18 jointly).
Persistent infection (persisting during at least six months or at least 12 months) with vaccine HPV types.

Search methods for identification of studies

We searched for papers in all languages and translations were undertaken, if necessary.

Electronic searches

We retrieved published studies from the Cochrane Central Register of Controlled Trials (CENTRAL the Cochrane Library), MEDLINE and Embase.

Cochrane Central Register of Controlled Trials (CENTRAL 2002 to 2017, Issue 5).  MEDLINE (2002 to June Week 1 2017).  Embase (2002 to 2017 week 24).

The search strategies for MEDLINE, CENTRAL and Embase are listed in Appendix 3, Appendix 4 and Appendix 5.

The search string for MEDLINE was saved in My NCBI, an electronic search tool developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine, which saves searches and automatically retrieves newer references not picked‐up at previous searches. An auto‐alert was set up in Embase.

The 'related articles' feature in PubMed was used, departing from the original included studies; similarly, Scopus was used to retrieve articles which cite the originally included studies.

We searched databases were searched from 2002 (the year of publication of the results of the first phase II trial) until June 2017.

Searching other resources

Registries of randomised trials

We searched the following registries to identify unpublished or ongoing trials: www.clinicaltrials.gov, www.isrctn.com, and www.cancer.gov/clinicaltrials.

Data on adverse effects published in the peer‐reviewed literature were complemented by searches in wwww.clinicaltrials.gov for the quadrivalent vaccine and on http://www.gsk‐clinicalstudyregister.com/ for the bivalent vaccine. We collected data for the outcomes of serious adverse events, all‐cause mortality and pregnancy outcomes from these sources and compared them with data extracted from the primary trial publications.

International public health organisations

We contacted international public health organisations that have investigated questions on HPV vaccine efficacy and safety or that have formulated recommendations on the use of HPV vaccines, to retrieve key documents. Concerned organisations included: the World Health Organization (WHO, Geneva), the US Centers for Disease Control and Prevention (CDC, Atlanta), the European Centre for Disease Prevention and Control (ECDC, Stockholm), and the International Agency for Research on Cancer (IARC, Lyon).

Handsearching

We handsearched the citation lists of included studies.

In addition, we searched the abstracts of the latest conferences of relevant scientific societies related to vaccination, virology (in particular the International Papillomavirus Society), paediatrics, and gynaecology for new or pending information not yet published in peer‐reviewed journals.

Correspondence

We contacted study authors to request results on effects separated by gender, if the reports only contained data combined for both genders.

Data collection and analysis

Selection of studies

We downloaded all titles and abstracts retrieved by electronic searching to a bibliographic database stored in Reference Manager. We added any references obtained by handsearching and removed any duplicates.

We (MA, CS and LX) independently verified inclusion and exclusion of eligible studies and discussed any disagreements. In case of doubt, the full‐text report was read. If no consensus could be reached, review author PMH was consulted. We documented reasons for exclusion.

Data extraction and management

For included studies, we extracted the following study characteristics and outcome data.

Study identification: first author, year of publication, journal, trial number.
Geographical area where the study was conducted.
Period when study was conducted.
Inclusion and exclusion criteria.
Characteristics of included participants (total number enrolled, age, number of previous sexual partners).
Initial HPV status (presence or absence of hrHPV DNA; presence or absence of DNA of the vaccine HPV types; serological status (presence of antibodies against vaccine HPV types) at enrolment). Differences in efficacy outcomes by initial HPV status will reflect protection in women or girls previously exposed, or not exposed to prior HPV infection.
Study design:
1. phase of the randomised trial (II or III);
2. type of vaccine evaluated (monovalent, bivalent, or quadrivalent);
3. control group: type of placebo or other vaccine administered;
4. time points (mean duration of follow‐up after first dose) at which outcomes were collected and reported;
5. study size at enrolment and at subsequent time points of follow‐up;
6. number of doses received;
7. scheduling of screening tests (HPV tests, cytology);
8. diagnostic algorithms used to confirm outcomes;
9. definition of study groups on which per‐protocol and intention‐to‐treat analyses were applied;
10. risk of bias in study design (see below: Assessment of risk of bias in included studies).
Outcomes, subdivided by (i) the association with vaccine HPV types and (ii) irrespective of HPV types:
1. outcome definition (including diagnostic criteria and assays);
2. results: number of participants allocated to each intervention group; number of missing values and absolute values required to compute effect measures (see Types of outcome measures);
3. data for the efficacy outcomes and short‐term adverse events relating to the injection procedures were collected from primary trial publications. For outcomes relating to serious adverse events, all‐cause mortality and pregnancy outcomes, data were cross‐checked between trial registries, study results websites, correspondence with investigators and the primary trial reports. The primary analysis used the data derived from the reports with the longest follow‐up time. A sensitivity analysis on serious adverse effects and mortality was restricted to data derived from reports published in peer‐reviewed journals.
Involvement of manufacturers.

We extracted data on outcomes as follows.

For dichotomous outcomes, we extracted the number of participants in each treatment arm who experienced the outcome of interest and the number of participants assessed at endpoint in order to estimate a risk ratio (RR) or risk difference (RD). Where possible, we also extracted the number of person‐years at risk in order to compute incidence rates and incidence rate ratios or differences.

We (MA, CS until 2011 and LX from 2012) independently extracted data onto a data abstraction form specially designed for the review. Differences between review authors were resolved by discussion or by appeal to a third review author (PMH) if necessary.

Assessment of risk of bias in included studies

We assessed the risk of bias in included RCTs using Cochrane's 'Risk of bias' tool and the criteria specified in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). This included assessment of:

the method used for randomisation to generate the sequence of participants allocated to the treatment arms;
allocation concealment;
blinding (of participants, healthcare providers;
blinding of outcome assessment;
reporting of incomplete outcome data for each outcome;
selective reporting of outcomes.

We (MA, CS and LX) independently applied the Cochrane 'Risk of bias' tool and differences were resolved by discussion or by appeal to a third review author (PMH). Results were presented in both a 'Risk of bias' graph and a 'Risk of bias' summary. We interpreted the results of meta‐analyses in the light of the findings with respect to risk of bias.

Measures of treatment effect

We computed risk ratios (RR) from the ratio of proportions or rates of events among vaccine recipients versus placebo recipients. In the literature, protection against HPV infection or cervical precancer is usually presented as vaccine efficacy (VE), VE = (1‐RR)*100. However, pooling of VE is not supported by the Review Manager (RevMan) software (Review Manager 2014). Where perfect efficacy corresponds with VE = 100%, the corresponding RR = 0; VE = 0% or RR = 1 means absence of protection. Negative VE or RR exceeding unity reflect adverse protection (vaccinated participants are more at risk than non‐vaccinated participants). When the 95% confidence interval contains unity, the protective effect is statistically insignificant. The number of participants needed to vaccinate (NNV) to avoid one outcome event was computed from the risk difference (NNV = 1/RD).

To show vaccination effects at population level, Cates plots were drawn, showing effects in 1000 vaccinated and 1000 non‐vaccinated women (Cates 2015).

Dealing with missing data

We contacted study authors or data owners to request data on the outcomes, separated by gender, if the reports only contained data combined for both genders in trials where both women and men were enrolled. We did not impute missing outcome data.

Assessment of heterogeneity

We assessed heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials that could not be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, if possible, by subgroup analyses. If there was evidence of substantial heterogeneity, we investigated and reported the possible reasons.

In order to avoid heterogeneity, we did not combine data series from participants with different baseline HPV status (presence of hrHPV DNA, presence of DNA of the HPV vaccine types). Age group and sexual history were investigated as potential sources that could explain possible heterogeneity.

Assessment of reporting biases

We planned to construct funnel plots and to perform regression tests to identify asymmetry in the meta‐analysis (Harbord 2009). However, since each meta‐analysis contained seven or fewer studies, this was not feasible. Instead, we performed meta‐regression to identify possible small‐study effects grouping studies in two categories: large (> = 3000 participants) and small (< 3000 participants).

Data synthesis

Random‐effects models with inverse variance weighting were applied using the RevMan 5 (DerSimonian 1986). From the pooled RR, VE was computed (VE = 1‐RR). Pooled risk differences were computed also for the 'Summary of findings' tables.

Subgroup analysis and investigation of heterogeneity

We performed separate analyses determined by the participant's HPV status as defined by the result of an HPV DNA tests at enrolment. Three groups were distinguished: a) initially hrHPV DNA negative, b) initially HPV16/18 DNA negative, and c) regardless of initial HPV DNA test results. Subgroup meta‐analyses were performed, if possible, using vaccine type and age group as a stratifying variable. We distinguished younger (15 to 26 years) from mid‐adult women (24 to 45 years), which were the two age groups assessed in the available randomised trials. If efficacy estimates were not significantly different by vaccine type, jointly pooled estimates were retained. Only when significant heterogeneity by vaccine types was noted, were separate efficacy estimates by vaccine type pooled. We used meta‐regression to investigate sources of heterogeneity such as serological status, study design items, study size and sexual history (Sharp 1998; Thompson 1999). The log relative risk (vaccinated versus placebo recipients) was used as the dependent variable. The antilog of coefficients of the meta‐regression yielded relative risk ratios (RRR). 95% confidence intervals around the RRR excluding unity indicated a statistically influential factor.

We assessed the influence of covariates, which were not defined uniformly throughout the trials, by Poisson regression in each trial concerned, separately and using person‐years at risk as an offset.

A posteriori analysis was performed to investigate vaccine efficacy in women who had received fewer than three doses of vaccine, by subtraction of the number of events and total number of participants who had received three doses from those who had received at least one dose. This was the only possible approach, since outcomes stratified by number of doses received, were not usually reported in the published papers.

Sensitivity analysis

We assessed the robustness of data collected for serious adverse events, all‐cause mortality and pregnancy outcomes based on the source of data. The primary analysis for these outcomes included data that we considered to represent the most complete follow‐up. As a sensitivity analysis we used data for these same outcomes that had only been reported in the published trial reports.

'Summary of findings' tables

We created 'Summary of findings' tables for three populations of interest.

Adolescent girls and women who were negative for hrHPV DNA at baseline
Adolescent girls and women who were negative for HPV16/18 DNA at baseline
Adolescent girls and women regardless of HPV DNA status at baseline

We included findings for the following outcomes for each population.

Cervical cancer
CIN2+ or CIN3+ associated with HPV16/18; any CIN2+ or CIN3+, irrespective of HPV types
AIS associated with HPV/16/18; any AIS irrespective of HPV types
All‐cause mortality (in all enrolled women)
Serious adverse events (in all enrolled women)

We included a fourth table summarising pregnancy outcomes as follows.

Spontaneous abortion/miscarriage
Elective termination/induced abortion
Spontaneous miscarriage
Babies born with congenital malformations

Since only randomised clinical trials were included in the review, the rating for each outcome started as high‐quality evidence and was downgraded for the following considerations according to GRADE guidance (Higgins 2011b).

Risk of bias
Inconsistency (both quantitative and qualitative)
Imprecision (relating to the width of the 95% confidence interval and number of participants in the analysis)
Indirectness
Publication bias

Results

Description of studies

Results of the search

The search in MEDLINE, Embase and CENTRAL, conducted after the publication of the updated protocol (Arbyn 2013), was updated up on 15 June 2017, which resulted in 1685 records and was completed with 112 citations of previously published reviews retrieved from Scopus and reports from the personal CERVIX bibliographic database, yielding 1797 records. After eliminating 34 duplicates, 1763 references were considered from which 1617 could be excluded based on title or objectives described in the abstract. Full reading of the abstracts and materials of 146 papers allowed exclusion of 90 reports. Finally, 56 relevant references describing characteristics and results of 26 randomised trials were selected for this review (Characteristics of included studies). The retrieval and selection of studies is summarised in the PRISMA flow chart in Figure 1. In addition, we included two reports of pooled analyses of included randomised controlled trials (RCTs) with original data (FUT I/II trials (ph3,4v); PATRICIA & CVT (ph3,2v)).

Flow diagram summarising the retrieval, inclusion and exclusion of relevant reports of randomised trials assessing the safety and effects of prophylactic HPV vaccines.

Details about the completeness of publication of HPV vaccination trials, registered in www.clinicaltrials.gov, can be found in Appendix 6. No additional studies could be retrieved from www.isrctn.com or www.cancer.gov/clinicaltrials.

Included studies

Twenty‐six randomised trials were identified that contained data on vaccine efficacy and/or safety, which all together enrolled 73,428 women. One trial (Phase2 trial (ph2,1v)) evaluated effects of a monovalent HPV16 vaccine, 18 trials evaluated the bivalent vaccine (African_2 country trial (ph3,2v); Chinese trial (ph3,2v)_ adolescent; Chinese trial (ph3,2v)_mid‐adult; Chinese trial (ph3,2v)_young; Co‐vaccination_dTpa_IPV trial (ph3,2v); Co‐vaccination_HAB trial (Ph3, 2v); Co‐vaccination_HepB trial (ph3, 2v); CVT (ph3,2v); Hong Kong trial (ph3,2v); Immunobridging(ph3,2v); Indian trial (ph3,2v); Japanese trial (ph2,2v); Korean trial (ph3,2v); Korean trial (ph3b,2v); Malaysian trial (ph3,2v); PATRICIA trial (ph3,2v); Phase2 trial (ph2,2v); VIVIANE trial (ph3,2v)) and seven others the quadrivalent vaccine (African_3 country trial (ph3,4v); FUTURE III trial (ph3,4v); FUTURE II trial (ph3,4v); FUTURE I trial (ph3,4v); Japanese trial (ph2,4v); Korean trial (ph2,4v); Phase2 trial (ph2,4v)). Six studies were phase II trials and 20 others were phase III trials. No phase I trials were included.

All trials were funded by the respective manufacturers of the vaccines, except one trial, which was financed by the National Cancer Instituite (CVT (ph3,2v)). The study size varied between 98 (African_3 country trial (ph3,4v)) and 18,644 (PATRICIA trial (ph3,2v)). The smaller studies (<1000) essentially assessed safety and immunogenicity (not assessed in this review) or only addressed protection against infection with the HPV vaccine types, whereas the larger phase III trials assessed also protection against cervical precancer (CIN2+, CIN3+ and AIS+). A listing of the 26 studies ranked by valency of the vaccine, phase (II or III) and alphabetic order is provided in Table 5.

1. Listing of included trials.

Valency	Phase	Number of trials	Appelation	N	Outcomes	Main References
Monovalent	II	1	Phase2 trial (ph2,1v)	2392	Efficacy, safety	Koutsky 2002 Mao 2006 Rowhani‐Rahbar 2009
Bivalent	II	2	Japanese trial (ph2,2v)	1040	Efficacy, safety	Konno 2010 Konno 2010a Konno 2014
	II	2	Phase2 trial (ph2,2v)	1113	Efficacy, safety	Harper 2004 Harper 2006 The GSK Study Group 2009 De Carvalho 2010
	III	16	African_2 country trial (ph3,2v)	676	Safety	Sow 2013
			Chinese trial (ph3,2v)_young	6051	Efficacy, safety	Zhu 2014
			Chinese trial (ph3,2v)_ adolescent	750	Safety	Zhu 2014a
			Chinese trial (ph3,2v)_mid‐adult	1212	Safety	Zhu 2014a
			Co‐vaccination_dTpa_IPV trial (ph3,2v)	494	Safety	Garcia‐Sicilia 2010
			Co‐vaccination_HAB trial (Ph3, 2v)	494	Safety	Pedersen 2012
			Co‐vaccination_HepB trial (ph3, 2v)	541	Safety	Schmeink 2011
			CVT (ph3,2v)	7466	Efficacy, safety	Herrero 2011 Kreimer 2011
			Hong Kong trial (ph3,2v)	294	Safety	Ngan 2010
			Immunobridging(ph3,2v)	2067	Safety	Medina 2010
			Indian trial (ph3,2v)	354	Safety	Bhatla 2010
			Korean trial (ph3,2v)	208	Safety	Kim 2010
			Korean trial (ph3b,2v)	321	Safety	Kim 2011
			Malaysian trial (ph3,2v)	271	Safety	Lim 2014
			PATRICIA trial (ph3,2v)	18,644	Efficacy, safety	Paavonen 2007 Paavonen 2009 Szarewski 2011 Wheeler 2011 Lehtinen 2012
			VIVIANE trial (ph3,2v)	5752	Efficay, safety,	Skinner 2014 Wheeler 2016
Quadrivalent	II	3	Japanese trial (ph2,4v)	1021	Safety	Yoshikawa 2013
			Korean trial (ph2,4v)	176	Safety	Kang 2008
			Phase2 trial (ph2,4v)	552	Efficacy, safety	Villa 2005 Villa 2006 Villa 2006a Olsson 2009
	III	4	African_3 country trial (ph3,4v)	98	Safety	Mugo 2015
			FUTURE I trial (ph3,4v)	5455	Efficacy, safety	Garland 2007
			FUTURE II trial (ph3,4v)	12,167	Efficacy, safety	FUTURE‐II 2007
			FUTURE III trial (ph3,4v)	3819	Efficacy, safety	Munoz 2009 Castellsagué 2011
Total		26		73,428

HPV vaccine effects on cervical lesions in adolescent girls and women who are hrHPV DNA negative at baseline
Patient or population: adolescent girls and women aged 15 to 26 years who are hrHPV negative before vaccination Setting: Europe, Asia Pacific countries, South & North America  Intervention: HPV vaccines (at least one dose of bivalent or quadrivalent vaccines) Comparison: Placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with HPV vaccination¹
Cervical cancer ‐ not measured	‐	‐	‐	‐	‐
CIN2+ associated with HPV16/18. Follow‐up: 3 to 5 years	164 per 10,000	2 per 10,000  (0 to 8)	RR 0.01  (0.00 to 0.05)	23,676  (3 RCTs)	⊕⊕⊕⊕  HIGH
CIN3+ associated with HPV16/18 Follow‐up: 3 to 5 years	70 per 10,000	0 per 10,000  (0 to 7)	RR 0.01  (0.00 to 0.10)	20,214  (2 RCTs)	⊕⊕⊕⊕  HIGH	Continuity correction
AIS associated with HPV16/18 Follow‐up: 3 to 5 years	9 per 10,000	0 per 10,000  (0 to 7)	RR 0.10  (0.01 to 0.82)	20,214  (2 RCTs)	⊕⊕⊕⊝  MODERATE ²	Continuity correction
Any CIN2+ irrespective of HPV type, bivalent or quadrivalent vaccine Follow‐up: 2 to 6 years	287 per 10,000	106 per 10,000  (72 to 158)	RR 0.37  (0.25 to 0.55)	25,180  (5 RCTs)	⊕⊕⊕⊕  HIGH	Substantial subgroup heterogeneity was observed (I²= 84.3%) for bi‐ and quadrivalent vaccines. So results are reported separately for the 2 vaccines (see next 2 rows).
Any CIN2+ irrespective of HPV type Follow‐up (bivalent): 3.5 to 6 years Follow‐up (quadrivalent): 3.5 years	Bivalent vaccine		RR 0.33 (0.25 to 0.43)	15,884 (4 RCTs)	⊕⊕⊕⊕  HIGH
	285 per 10,000	94 per 10,000 (71 to 122)
	Quadrivalent vaccine		RR 0.57 (0.44 to 0.76)	9296 (1 RCT)	⊕⊕⊕⊝  MODERATE³
	291 per 10,000	166 per 10,000 (128 to 221)
Any CIN3+ irrespective of HPV type, bivalent or quadrivalent vaccine Follow‐up: 3.5 to 4 years	109 per 10,000	23 per 10,000  (4 to 120)	RR 0.21  (0.04 to 1.10)	20,719  (3 RCTs)	⊕⊕⊕⊝  MODERATE ³	Substantial subgroup heterogeneity was observed (I² = 84.3%) for bi‐ and quadrivalent vaccines. So results are reported separately for the 2 vaccines (see next 2 rows).
Any CIN3+ irrespective of HPV type Follow‐up (bivalent): 4 years Follow‐up (quadrivalent): 3.5 years	Bivalent vaccine		RR 0.08 (0.03 to 0.23)	11,423 (2 RCTs)	⊕⊕⊕⊕  HIGH
	81 per 10,000	6 per 10,000 (3 to 19)
	Quadrivalent vaccine		RR 0.54 (0.36 to 0.82)	9296 (1 RCT)	⊕⊕⊕⊝  MODERATE³
	143 per 10,000	77 per 10,000 (51 to 117 )
Any AIS irrespective of HPV type    Follow‐up: 3 to 5 years	10 per 10,000	0 per 10,000  (0 to 8)	RR 0.10  (0.01 to 0.76)	20,214  (2 RCTs)	⊕⊕⊕⊝  MODERATE ²	Continuity correction
¹The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). When risk in vaccine group is zero, the 95% CI is computed using an exact binomial method.    AIS: adenocarcinoma in situ; CI: Confidence interval; CIN: cervical intraepithelial neoplasia; RR: Risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: 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  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

HPV vaccine adverse pregnancy outcomes (regardless of DNA status and age)
Patient or population: adolescent girls and women aged 15 to 45 years who became pregnant during the study  Setting: Europe, Asia Pacific, North, Central and South America  Intervention: HPV vaccines (bivalent or quadrivalent vaccines)  Comparison: Placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with HPV vaccines
Spontaneous abortion/miscarriage Follow‐up: 1 to 7 years	Study population		RR 0.88  (0.68 to 1.14)	8618  (9 RCTs)	⊕⊕⊕⊕  HIGH
	1618 per 10,000	1,424 per 10,000  (1,100 to 1844)
Elective termination/induced abortion Follow‐up: 1 to 7 years	Study population		RR 0.90  (0.80 to 1.02)	10,909  (9 RCTs)	⊕⊕⊕⊕  HIGH ¹
	931 per 10,000	838 per 10,000  (745 to 950)
Stillbirth Follow‐up: 1 to 3.5 years	Study population		RR 1.12  (0.68 to 1.83)	8754  (6 RCTs)	⊕⊕⊕⊝  MODERATE ²
	70 per 10,000	78 per 10,000  (48 to 128)
Babies born with congenital malformations Follow‐up: 3 to 7 years	Study population		RR 1.22  (0.88 to 1.69)	9252  (5 RCTs)	⊕⊕⊕⊝  MODERATE ²
	205 per 10,000	250 per 10,000  (180 to 346)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: 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  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Outcomes and exposure subgroups	Absolute risk / per 10,000		Relative risk  (95% CI)	Vaccine efficacy (95% CI)	Risk difference/ per 10,000 (95% CI)	No of Participants  (studies)	Certainty of evidence  (GRADE)*
Outcomes and exposure subgroups	Placebo	Vaccinated	Relative risk  (95% CI)	Vaccine efficacy (95% CI)	Risk difference/ per 10,000 (95% CI)	No of Participants  (studies)	Certainty of evidence  (GRADE)*
1. High‐grade cervical lesions in women who were hrHPV DNA negative at baseline
Analysis 1.1 CIN2+ associated with HPV16/18, at least 1 dose, age 15‐26 years	164	2	0.01 (0.00 to 0.05)	99% (95% to 100%)	162 (157 to 164)	23,676  (3 studies)	⊕⊕⊕⊕ high
Analysis 1.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years	197	2	0.01 (0.00 to 0.09)	99% (91% to 100%)	195 (179 to 197)	9296 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 1.3 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years	70	0*	0.01 (0.00 to 0.10)	99% (90% to 100%)	70 (63 to 70)	20,214 (2 studies)	⊕⊕⊕⊕ high
Analysis 1.4 CIN3+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years	94	0*	0.01 (0.00 to 0.18)	99% (82% to 100%)	94 (77 to 94)	9296 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 1.5 AIS associated with HPV16/18, at least 1 dose, age 15‐26 years	9	0*	0.10 (0.01 to 0.82)	90% (18% to 99%)	9 (2 to 9)	20,214  (2 studies)	⊕⊕⊕⊝  moderate⁴
Analysis 1.6 AIS associated with HPV6/11/16/18m at least 1 dose, age 15‐26 years	6	0*	0.14 (0.01 to 2.8)	86% (‐180% to 99%)	6 (‐12 to 6)	9296 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 1.7.1 Any CIN2+ irrespective of HPV types, at least 1 dose of the bivalent vaccine, age 15‐26 years	285	94	0.33 (0.25 to 0.43)	67% (57% to 75%)	191 (163 to 214)	15,884 (4 studies)	⊕⊕⊕⊕ high
Analysis 1.7.2 Any CIN2+ irrespective of HPV types, at least 1 dose of the quadrivalent vaccine, age 15‐26 years	291	166	0.57 (0.44 to 0.76)	43% (24 to 56%)	125 (70 to 163)	9296 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 1.8.1 Any CIN3+ irrespective of HPV types, at least 1 dose of the bivalent vaccine, age 15‐26 years	81	6	0.08 (0.03 to 0.23)	92% (77% to 97%)	74 (62 to 78)	11,423 (2 studies)	⊕⊕⊕⊕  high
Analysis 1.8.2 Any CIN3+ irrespective of HPV types, at least 1 dose of the quadrivalent vaccine, age 15‐26 years	143	77	0.54 (0.36 to 0.82)	46% (17% to 64%)	66 (26 to 92)	9296 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 1.9 Any AIS irrespective of HPV types, at least 1 dose	10	0*	0.10 (0.01 to 0.76)	90% (24% to 99%)	10 (2 to 10)	20,214  (2 studies)	⊕⊕⊕⊝  moderate⁴
2. High‐grade cervical lesions in women who were HPV16/18 negative at baseline
Analysis 2.1.1 CIN2+ associated with HPV16/18, 3 doses, age 15‐26 years	74	5	0.07 (0.03 to 0.15)	93% (85% to 97%)	69 (63 to 72)	36,579 (6 studies)	⊕⊕⊕⊕ high
Analysis 2.1.2 CIN2+ associated with HPV16/18, 3 doses, 24‐45 years	36	6	0.16 (0.04 to 0.74)	84% (26% to 96%)	30 (9 to 34)	6797 (2 studies)	⊕⊕⊕⊝  moderate⁴
Analysis 2.2.1 CIN2+ associated with HPV16/18, at least 1 dose, 15‐26 years	113	6	0.05 (0.03 to 0.10)	95% (90% to 97%)	107 (102 to 110)	34,478 (6 studies)	⊕⊕⊕⊕ high
Analysis 2.2.2 CIN2+ associated with HPV16/18, at least 1 dose, age 24‐45 years	45	14	0.30 (0.11 to 0.81)	70% (19% to 89%)	32 (9 to 40)	7552 (2 studies)	⊕⊕⊕⊝  moderate⁴
Analysis 2.3.1 CIN2+ associated with HPV16/18, 1 or 2 doses, 15‐26 years***	436	44	0.10 (0.04 to 0.26)	90% (74% to 96%)	392 (323 to 418)	2958 (5 studies)	⊕⊕⊝⊝ low^1$
Analysis 2.3.2 CIN2+ associated with HPV16/18, 1 or 2 doses, age 24‐45 years***	134	82	0.61 (0.14 to 2.67)	39% (‐167% to 86%)	52 (‐2245 to 115)	755 (2 studies)	⊕⊝⊝⊝  very low^1$,4
Analysis 2.4 CIN2+ associated with HPV6/11/16/18, 3 doses, age 15‐45 years	99	6	0.06 (0.01 to 0.61)	94% (39% to 99%)	93 (39 to 98)	7664 (2 studies)	⊕⊕⊕⊝  moderate⁴
Analysis 2.4.1 CIN2+ associated with HPV6/11/16/18, 3 doses, age 15‐26 years	142	0*	0.02 (0.00 to 0.25)	98% (75% to 100%)	142 (93 to 190)	4499 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 2.4.2 CIN2+ associated with HPV6/11/16/18, 3 doses, age 24‐45 years	38	6	0.17 (0.02 to 1.39)	83% (‐39% to 98%)	32 (‐1 to 32)	3165 (1 study)	⊕⊕⊝⊝  low^3,4
Analysis 2.5.1 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years	160	0*	0.01 (0.00 to 0.19)	99% (81% to 100%)	160 (130 to 159)	5351 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 2.5.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 24‐45 years	44	16	0.37 (0.10 to 1.41)	63% (‐41% to 90%)	28 (‐18 to 40)	3629 (1 study)	⊕⊕⊕⊝  moderate^3,4
Analysis 2.6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 15‐45 years***	199	48	0.24 (0.01 to 5)	76% (‐400% to 99%)	151 (‐795 to 197)	1316 (2 studies)	⊕⊝⊝⊝  very low^1$,4
Analysis 2.6.1 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 15‐26 years***	258	0*	0.04 (0.00 to 0.74)	96% (26% to 100%))	258 (108 to 409)	852 (1 study)	⊕⊝⊝⊝  very low^1$,3,4
Analysis 2.6.2 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 24‐45 years***	88	85	0.97 (0.14 to 6.80)	3% (‐580% to 86%)	3 (‐165 to 171)	464 (1 study)	⊕⊝⊝⊝  very low^1$,3,4
Analysis 2.7 CIN3+ associated with HPV16/18, 3 doses, age 15‐26 years	40	3	0.07 (0.02 to 0.29)	93% (71% to 98%)	37 (28 to 39)	29,720 (3 studies)	⊕⊕⊕⊕  high
Analysis 2.8 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years	57	3	0.05 (0.02 to 0.14)	95% (86% to 98%)	54 (49 to 56)	33,199 (3 studies)	⊕⊕⊕⊕ high
Analysis 2.9 CIN3+ associated with HPV16/18, 1 or 2 doses, age 15‐26 years***	200	12	0.06 (0.01 to 0.24)	94% (26% to 100%)	188 (152 to 198)	3479 (3 studies)	⊕⊕⊝⊝ low^1$
Analysis 2.10 AIS+ associated with HPV16/18, 3 doses, age 15‐26 years	8	0*	0.12 (0.02 to 0.70)	88% (36% to 99%)	8 (2 to 8)	29,707 (3 studies)	⊕⊕⊕⊝  moderate⁴
Analysis 2.11 AIS+ associated with HPV16/18, at least 1 dose, age 15‐26 years	12	0*	0.09 (0.01 to 0.72)	81% (28% to 99%)	12 (3 to 12)	17,079 (2 studies)	⊕⊕⊕⊝  moderate⁴
Analysis 2.12 AIS+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses, age 15‐26 years***	29	0*	0.15 (0.01 to 2.97)	85% (‐197% to 99%)	29 (‐57 to 29)	2015 (2 studies)	⊕⊝⊝⊝  very low^1$,4
Analysis 2.13 CIN2+ irrespective of HPV types, 3 doses, age 15‐26 years	166	66	0.40 (0.25 to 0.64)	60% (36% to 75%)	99 (60 to 124)	7320 (3 studies)	⊕⊕⊕⊕ high
Analysis 2.14 CIN2+ irrespective of HPV types, at least 1 dose, age 15‐26 years	231	95	0.41 (0.32 to 0.52)	58% (46% to 67%)	136 (111 to 157)	19,143 (3 studies)	⊕⊕⊕⊕ high
Analysis 2.15 CIN2+ irrespective of HPV types, 1 or 2 doses, age 20‐25 years***	1000	710	0.71 (0.15 to 3.38)	29% (‐238% to 85%)	290 (‐2,380 to 850)	34 (1 study)	⊕⊝⊝⊝  very low^1$,3,4
3. High‐grade cervical lesions in all women regardless of HPV DNA status at baseline**
Analysis 3.1.1 CIN2+ associated with HPV16/18, at least 1 dose, age 15‐26 years	341	157	0.46 (0.37 to 0.57)	54% (43% to 63%)	184 (147 to 215)	34,852  (3 studies)	⊕⊕⊕⊕ high
Analysis 3.1.2 CIN2+ associated with HPV16/18, at least 1 dose, age 24‐45 years	157	116	0.74 (0.52 to 1.05)	26% (‐5% to 48%)	41 (‐8 to 75)	9200 (2 studies)	⊕⊕⊕⊝ moderate⁴
Analysis 3.2.1 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years	436	217	0.50 (0.42 to 0.59)	50% (41% to 58%)	219 (166 to 272)	17,160 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 3.2.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 24‐45 years	145	113	0.78 (0.44 to 1.37)	22% (‐37% to 56%)	143 (72 to 204	3723 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 3.3 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years	165	91	0.55 (0.43 to 0.68)	74% (55% to 91%)	74 (55 to 91)	34,562  (2 studies)	⊕⊕⊕⊕ high
Analysis 3.4 CIN3+ associated with HPV16/18, 1 or 2 doses, age 15‐26 years***	230	124	0.54 (0.43 to 0.68)	46% (32% to 57%)	106 (74 to 131)	17,160 (1 study)	⊕⊕⊝⊝  low^1,3
Analysis 3.5 AIS associated with HPV16/18, at least 1 dose, age 15‐26 years	14	5	0.36 (0.17 to 0.78)	64% (22% to 83%)	9 (3 to 12)	34,562  (2 studies)	⊕⊕⊕⊕ high
Analysis 3.6 AIS associated with HPV6/11/16/18, at least 1 dose, age 15‐45 years	15	6	0.40 (0.16 to 0.98)	60% (2% to 84%)	9 (0 to 13)	20,830 (1 study)	⊕⊕⊕⊝  moderate^3,4
Analysis 3.7.1 Any CIN2+ irrespective of HPV types, at least 1 dose, age 15‐26 years	559	391	0.70 (0.58 to 0.85)	30% (15% to 42%)	168 (84 to 235)	35,779  (4 studies)	⊕⊕⊕⊕ high
Analysis 3.7 2 Any CIN2+ irrespective of HPV types, at least 1 dose, age 24‐45 years	342	356	1.04 (0.83 to 1.30)	‐4% (‐30% to 17%)	‐14 (‐103 to 58)	9287 (2 studies)	⊕⊕⊝⊝  moderate⁴
Analysis 3.8 Any CIN3+ irrespective of HPV types, at least 1 dose, age 18‐26 years, bivalent vaccine	188	103	0.55 (0.43 to 0.71)	45% (29% to 57%)	84 (54 to 1107)	18,329 (2 studies)	⊕⊕⊕⊕ high
Analysis 3.8 Any CIN3+ irrespective of HPV types, at least 1 dose, age 15‐26 years, quadrivalent vaccine	349	283	0.81 (0.69 to 0.96)	19% (4% to 31%)	66 (14 to 108)	17,160 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 3.9 Any AIS irrespective of HPV types, at least 1 dose, age 15‐26 years	17	5	0.32 (0.15 to 0.67)	68% (33% to 0.85%)	11 (6 to 14)	34,562  (2 studies)	⊕⊕⊕⊕ high
4. HPV16/18 infection in women who were hrHPV DNA negative at baseline
Analysis 4.1 Incident HPV16/18 infection, 3 doses, age 18‐26 years	2,457	147	0.06 (0.02 to 0.20)	94% (80% to 98%)	2,310 (1,966 to 2,408)	368 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 4.2 Persistent HPV16/18 infection(6M), 3 doses, age 15‐26 years	971	29	0.02 (0.00 to 0.35)	97% (57% to 100%)	942 (554 to 971)	368 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 4.3 Persistent HPV16/18 infection(6M), at least 1 dose, age 18‐25 years	96	7	0.07 (0.05 to 0.09)	93% (81% to 95%)	90 (88 to 91)	10,826 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 4.4 Persistent HPV16/18 infection(12M), 3 doses, age 15‐26 years	571	23	0.04 (0.00 to 0.73)	96% (27% to 100%)	549 (154 to 571)	368 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 4.5 Persistent HPV16/18 infection(12M), at least 1 dose, age 15‐26 years	462	37	0.08 (0.05 to 0.12)	92% (88% to 95%)	425 (406 to 439)	14,153 ( 2 studies)	⊕⊕⊕⊕ high
5. HPV16/18 infection in women who were HPV16/18 negative at baseline
Analysis 5.1 Incident HPV16/18 infection, 3 doses, age 15‐26 years	474	81	0.17 (0.10 to 0.31)	87% (78% to 92%)	412 (369 to 436)	8,034 (4 studies)	⊕⊕⊕⊕ high
Analysis 5.2 Incident HPV16/18 infection, at least 1 dose, age 15‐26 years	1,326	305	0.23 (0.14 to 0.37)	81% (71% to 88%)	1,074 (941 to 1,167)	23,872 (5 studies)	⊕⊕⊕⊕ high
Analysis 5.3 Incident HPV16/18 infection, 1 or 2 dose, age 15‐26 years***	2,568	1207	0.47 (0.26 to 0.84)	74% (31% to 90%)	1,901 (796 to 2,311)	331 (3 studies)	⊕⊕⊕⊝ moderate¹
Analysis 5.4.1 Persistent HPV16/18 infection (6M), 3 doses, age 15‐26 years	581	35	0.06 (0.05 to 0.08)	94% (91% to 95%)	546 (534 to 552)	27,385 (6 studies)	⊕⊕⊕⊕ high
Analysis 5.4.2 Persistent HPV16/18 infection (6M), 3 doses, age 24‐45 years	350	38	0.11 (0.06 to 0.20)	89% (80% to 94%)	311 (280 to 329)	6728 (2 studies)	⊕⊕⊕⊝  moderate⁴
Analysis 5.5.1 Persistent HPV16/18 infection (6M), at least 1 dose, age 15‐26 years	657	66	0.10 (0.08 to 0.13)	90% (87% to 92%)	591 (572 to 605)	22,803 (4 studies)	⊕⊕⊕⊕ high
Analysis 5.5.2 Persistent HPV16/18 infection (6M), at least 1 dose, age 24‐45 years	441	75	0.17 (0.10 to 0.29)	83% (71% to 90%)	366 (313 to 397)	7520 (2 studies)	⊕⊕⊕⊕ high
Analysis 5.6.1 Persistent HPV16/18 infection (6M), 1 or 2 doses, age 15‐26 years***	996	119	0.12 (0.03 to 0.42)	88% (58% to 97%)	876 (577 to 966)	437 (2 studies)	⊕⊕⊝⊝  low^1,4
Analysis 5.6.2 Persistent HPV16/18 infection (6M), 1 or 2 doses, age 24‐45 years***	1,221	379	0.31 (0.18 to 0.54)	69% (46% to 82%)	843 (562 to 1002)	792 (2 studies)	⊕⊕⊕⊝ moderate¹
Analysis 5.7 Persistent HPV6/11/16/18 infection (6M), 3 doses	518	62	0.12 (0.06 to 0.21)	88% (79% to 94%)	456 (409 to 487)	4008 (2 studies)	⊕⊕⊕⊕ high
Analysis 5.8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose	907	118	0.13 (0.05 to 0.37)	87% (63% to 95%)	789 (571 to 862)	4129 (2 studies)	⊕⊕⊕⊕ high
Analysis 5.9 Persistent HPV16/18 infection (12M), 3 doses	297	27	0.09 (0.06 to 0.13)	91% (87% to 94%)	270 (258 to 279)	22,267 (4 studies)	⊕⊕⊕⊕ high
Analysis 5.10 Persistent HPV16/18 infection (12M), at least 1 dose	365	58	0.16 (0.01 to 0.13)	84% (87% to 99%)	306 (292 to 361)	29,464 (5 studies)	⊕⊕⊕⊕ high
Analysis 5.11 Persistent HPV16/18 infection (12M), 1 or 2 doses***	205	27	0.13 (0.06 to 0.33)	87% (67% to 94%)	178 (137 to 193)	3912 (3 studies)	⊕⊕⊕⊝ moderate¹
6. HPV16/18 infection regardless of HPV DNA status at baseline**
Analysis 6.1 Incident HPV16/18 infection, at least 1 dose, age 15‐26 years	807	194	0.24 (0.17 to 0.33)	76% (67% to 83%)	613 (541 to 670)	4210 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 6.2.1 Persistent HPV16/18 infection (6M), at least 1 dose, age 15‐26 years	1,359	598	0.44 (0.38 to 0.51)	56% (49% to 62%)	761 (666 to 842)	25,199 (2 studies)	⊕⊕⊕⊕ high
Analysis 6.2.2 Persistent HPV16/18 infection (6M), at least 1 dose, age 24‐45 years	642	366	0.57 (0.47 to 0.69)	43% (31% to 53%)	276 (199 to 341)	8648 (2 studies)	⊕⊕⊕⊕ high
Analysis 6.3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose, age 24‐45 years	1,136	591	0.52 (0.42 to 0.65)	48% (35% to 58%)	545 (398 to 659)	3713 (1 study)	⊕⊕⊕⊝  moderate³
Analysis 6.4 Persistent HPV16/18 infection (12M), at least 1 dose, age 15‐26 years	861	396	0.46 (0.40 to 0.54)	54% (46% to 60%)	465 (396 to 516)	24,785 (2 studies)	⊕⊕⊕⊕ high
CI: Confidence interval; RR: Risk Ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect. The attribution of "high quality" depends on the following conditions: well‐conducted randomised trials, with consistent findings, direct outcome, precise estimates (narrow confidence intervals), absence of reporting bias (Guyatt 2008). Moderate quality:* Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Outcome	Initial HPV status at enrolment
Outcome	hrHPV negative	Regardless of HPV status
Lesions associated with HPV16/18	NNV (95% CI)	NNV (95% CI)
CIN2+	62 (61 to 64)	54 (46 to 68)
CIN3+	204 (149 to 333)	135 (110 to 263)
AIS+	1111 (714 to 5000)	1111 (625 to 3333)
Lesions irrespective of HPV types	NNV (95% CI)	NNV (95% CI)
CIN2+	60 (50 to 76)	68 (52 to 97)
CIN3+	141 (106 to 208)	133 (94 to 227)
AIS+	1000 (556 to 10,000)	833 (526 to 2000)

Outcomes	Absolute risk/ per 10,000		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	placebo	vaccinated	Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)
Analysis 7.1Overall local/injection site adverse events	6847	8080	1.18 (1.16 to 1.20)	18,113  (8 studies)	⊕⊕⊕⊝  moderate²
Analysis 7.2Pain at injection site	6505	8782	1.35 (1.23 to 1.49)	25,691  (13 studies)	⊕⊕⊕⊝  moderate²
Analysis 7.3Swelling at injection site	1582	2737	1.73 (1.32 to 2.27)	22,106  (9 studies)	⊕⊕⊕⊝  moderate²
Analysis 7.4Redness at injection site	1938	3333	1.72 (1.50 to 1.97)	19,996  (6 studies)	⊕⊕⊕⊝  moderate²
Analysis 7.5Overall systematic event and general symptoms	6102	6224	1.02 (0.98 to 1.07)	18,191  (8 studies)	⊕⊕⊕⊝  moderate²
Analysis 7.6Serious adverse events	605	611	1.01 (0.95 to 1.07)	6978  (21studies)	⊕⊕⊕⊕  high
Analysis 7.7Deaths	11	13	1.25 (0.81 to 1.93)	71,452 (23 studies)	⊕⊕⊝⊝  low^2,4,†
Analysis 8.1Normal infant	7171	7171	1.00 (0.97 to 1.02)	8782  (8 studies)	⊕⊕⊕⊕  high
Analysis 8.2Spontaneous abortion/miscarriage	1618	1424	0.88 (0.68 to 1.14)	8618  (9 studies)	⊕⊕⊕⊕  high
Analysis 8.3Elective termination/induced abortion	931	838	0.90 (0.80 to 1.02)	10.909  (9 studies)	⊕⊕⊕⊕  high
Analysis 8.4Stillbirth	70	78	1.12 (0.68 to 1.83)	8754  (6 studies)	⊕⊕⊕⊝⁴  moderate
Analysis 8.5Abnormal infant	205	250	1.22 (0.88 to 1.69)	9252  (5 studies)	⊕⊕⊕⊝⁴  moderate
CI: Confidence interval; RR: Risk Ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect. The attribution of "high quality" depends on the following conditions: well‐conducted randomized trials, with consistent findings, direct outcome, precise estimates (narrow confidence intervals), absence of reporting bias (Guyatt 2008). Moderate quality:* Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

ID	Group	Death causes
1	C	Pulmonary thromboembolism with background of acute lymphoblastic leukaemia
2	V	Breast cancer
3	V	Pulmonary tuberculosis
4	V	Thyrotoxicosis
5	V	Cerebral haemorrhage subsequent to hypertension
6	V	Pericarditis on a background of lupus erythematosus
7	V	Nasopharyngeal cancer with metastases to brain
8	V	Pulmonary embolism after intervention for uterine myoma
RR of deaths in vaccine vs placebo arm (7 over 1,890 vs 1 over 1888): RR = 6.99 (95% CI 0.86 to 56.78), 2‐sided p_exact=0.070. The age at death varied between 29 and 45 years, seven of the deaths occurred in the Philippines and one in Columbia. All participants received three doses of HPV vaccine or placebo except one who received only two doses of vaccine. The time interval between last dose and date at death ranged between 6 and 37 months.

Patient	Cause of death	Group	Age	Country	Source
1	Breast cancer metastatic	V	47	Canada	1
2	Suicide	V	47	Mexico	1
3	Lower respiratory tract infection and sepsis*	C	55	Mexico	1
4	Cervix cancer metastatic**	V	45	Mexico	1
5	Interstitial lung disease	V	41	Mexico	1
6	Breast cancer	***	32	Mexico	1***
7	Suicide	V	41	Mexico	1
8	Cardiac valve disease and liver disorder*	C	38	Mexico	1
9	Drug hypersensitivity and acute renal failure*	V	46	Peru	1
10	Cardiorespiratory arrest	C	44	Phillipines	1
11	Acute myocardial infarction	V	31	Phillipines	1
12	Multiple myeloma and pulmonary embolism*	V	50	Phillipines	1
13	Homicide	V	32	Phillipines	1
14	Bronchopneumonia	V	40	Singapore	1
15	Lung neoplasm malignant	V	41	Thailand	1
16	Suicide	V	28	USA	1
17	Glioblastoma multiforme	V	45	USA	1
18	Anaplastic astrocytoma	C	43	****	2
19	Nasopharyngeal cancer	C	41	****	2
Remarks
*	Multiple death causes
**	This woman had normal cytology but was HPV‐18 DNA‐positive at study entry (May 2006). At the next scheduled cytology testing at Month 12 (April 2007), the cytology finding was atypical squamous cells cannot exclude high‐grade squamous intraepithelial lesion. She was diagnosed with metastatic cervical cancer in May 2007 (approximately 7 months after receiving the third dose of vaccine or control) and died in July 2008
***	One case of death due to breast cancer reported in the 48 month report (Skinner 2014) had to be excluded from the analysis (Wheeler 2016).
****	Two additional cases of death occurring in the control arm were reported in the 84‐month report (Wheeler 2016). The country for these two cases was not reported.

Trial	Target age group	Age category	Reported age sub‐groups
Phase2 trial (ph2,1v)	16‐23	younger	none
Phase2 trial (ph2,2v)	15‐25	younger	none
Phase2 trial (ph2,4v)	16‐23	younger	none
Japanese trial (ph2,2v)	20‐25	younger	none
PATRICIA trial (ph3,2v)	15‐25	younger	15‐17, 18‐20, 21‐25
CVT (ph3,2v)	18‐25	younger	18‐19, 20‐21, 22‐23, 24‐25
VIVIANE trial (ph3,2v)	26+	older	26‐35, 36‐45, 46+
FUTURE I trial (ph3,4v)	16‐24	younger	none
FUTURE II trial (ph3,4v)	15‐26	younger	none
FUTURE III trial (ph3,4v)	25‐45	older	none

Outcome	Age	Event/N Vaccine	Event/N Placebo	Relative risk (95% CI)	Vaccine efficacy % (95% CI)	P value for linear effect of age
In women with hrHPV DNA negative status at baseline
CIN2+ associated with HPV16/18	15‐17	1/1997	53/2022	0.02 (0.00 to 0.14)	98% (86 to 100%)	0.995
	18‐20	0/1096	27/1144	0.02 (0.00 to 0.32)	98% (68 to 100%)
	21‐25	0/2363	17/2281	0.03 (0.00 to 0.47)	97% (53 to 100%)
CIN2+ irrespective of HPV types	15‐17	34/1997	101/2022	0.34 (0.23 to 0.50)	66% (50 to 77%)	0.355
	18‐20	10/1096	38/1144	0.27 (0.14 to 0.55)	73% (45 to 86%)
	21‐25	17/2363	33/2281	0.50 (0.28 to 0.89)	50% (11 to 72%)
CIN3+ associated with HPV16/18	15‐17	0/1997	14/2022	0.04 (0.00 to 0.61)	96% (39 to100%)	1.000
	18‐20	0/1096	8/1144	0.07 (0.00 to 1.13)	93% (‐13 to 100%)
	21‐25	0/2363	5/2281	0.10 (0.00 to 1.74)	90%(‐74 to 100%)
CIN3+ irrespective of HPV types	15‐17	2/1997	24/2022	0.08 (0.02 to 0.36)	92% (64 to 98%)	0.488
	18‐20	1/1096	11/1144	0.09 (0.01 to 0.73)	91% (27 to 99%)
	21‐25	0/2363	9/2281	0.05 (0.00 to 0.92)	95% (8 to 100%)
Persistent HPV16/18 infection (6M)	15‐17	14/1989	303/2020	0.05 (0.03 to 0.08)	95% (92 to 97%)	0..042
	18‐20	9/1090	110/1125	0.08 (0.04 to 0.17)	92%(83 to 96%)
	21‐25	12/2338	108/2249	0.11 (0.06 to 0.19)	89% (81 to 94%)
Regardless of women’s baseline HPV DNA status
CIN2+ associated with HPV16/18	15‐17	21/2882	100/2892	0.21 (0.13 to 0.24)	79% (66 to 87%)	0.000
	18‐20	23/1871	66/1908	0.36 (0.22 to 0.57)	64% (43 to 78%)
	21‐25	46/3929	62/3898	0.74 (0.50 to 1.08)	26% (‐8 to 50%)
CIN2+ irrespective of HPV types	15‐17	112/2882	200/2892	0.56 (0.45 to 0.70)	44% (30 to 55%)	0.006
	18‐20	62/1871	105/1908	0.60 (0.44 to 0.82)	40% (18 to 56%)
	21‐25	113/3929	123/3898	0.91 (0.09 to 1.17)	9% (‐17 to 29%)
CIN3+ associated with HPV16/18	15‐17	7/2882	36/2892	0.20 (0.09 to 0.44)	80% (56 to 91%)	0.000
	18‐20	13/1871	30/1908	0.44 (0.23 to 0.84)	56% (16 to 77%)
	21‐25	31/3929	28/3898	1.10 (0.66 to 1.83)	‐10% (‐83 to 34%)
CIN3+ irrespective of HPV types	15‐17	21/2882	61/2892	0.35 (0.21 to 0.57)	65% (43 to 79%)	0.008
	18‐20	22/1871	44/1908	0.51 (0.31 to 0.85)	49% (15 to 69%)
	21‐25	43/3929	53/3898	0.80 (0.54 to 1.20)	20% (‐20 to 46%)
Persistent HPV16/18 infection (6M)	15‐17	167/2916	588/2920	0.28 (0.24 to 0.34)	72% (66 to 76%)	0.000
	18‐20	143/1925	283/1961	0.51 (0.43 to 0.62)	49% (38 to 57%)
	21‐25	194/4009	356/3979	0.54 (0.46 to 0.64)	46% (36 to 54% )

Outcome	Age	Vaccine	Placebo	Relative risk (95% CI)	Vaccine efficacy (95% CI)	P value for linear effect of age
In women with HPV16/18 DNA negative status at baseline cohort
Persistent HPV16/18 infection (6M)	18‐19	1/825	51/870	0.02 (0.00 to 0.10)	98% (90% to 100%)	0.145
	20‐21	3/659	36/649	0.08 (0.02 to 0.24)	92% (76% to 98%)
	22‐23	2/588	36/625	0.06 (0.00 to 0.20)	94% (80% to 100%)
	24‐25	3/563	20/533	0.14 (0.03 to 0.44)	86% (56% to 97%)
Regardless if women’s baseline HPV DNA status
Persistent HPV16/18 infection (6M)	18‐19	47/1193	165/1,244	0.30 (0.21 to 0.41)	70% (59% to 79%)	0.000
	20‐21	64/946	134/905	0.46 (0.34 to 0.61)	54% (39% to 66%)
	22‐23	59/818	112/848	0.55 (0.40 to 0.75)	45% (25% to 60%)
	24‐25	61/770	75/742	0.78 (0.56 to 1.99)	22 %(‐9.9 to 44%)

Initial HPV DNA/ status	Serology status	Vaccine	Placebo	Relative Risk (95% CI)	Relative Risk ratio
FUTURE I trial (ph3,4v) (Garland 2007)*
DNA(‐)	Sero‐	0/2,241	32/2258	0.00 (0.02 to 0.26)	15.93
DNA(‐)	Sero+	0/377	2/379	0.25 (0.01 to 5.20)	15.93
DNA(+)	Sero‐	27/232	31/213	0.80 (0.49 to 1.29)	1.50
DNA(+)	Sero+	41/156	30/137	1.20 (0.80 to 1.81)	1.50
FUTURE II trial (ph3,4v) (FUTURE‐II 2007)**
DNA(‐)	Sero‐	0/5,305	28/5260	0.02(0.00 to 0.14)	7.41
DNA(‐)	Sero+	0/498	4/524	0.13 (0.01 to 2.43)	7.41
DNA(+)	Sero‐	33/423	35/402	0.90 (0.57 to 1.41)	1.12
DNA(+)	Sero+	47/298	52/332	1.01 (0.70 to 1.45	1.12
PATRICIA trial (ph3,2v) (Paavonen 2009)**
DNA(‐)	Sero‐	5/8709	92/8112	0.05 (0.02 to 0.12)	6.16
DNA(‐)	Sero+	3/1710	10/1777	0.31 (0.09 to 1.13)	6.16
DNA(+)	Sero‐	20/309	29/293	0.65 (0.38 to 1.13)	1.70
DNA(+)	Sero+	53/333	44/307	1.11 (0.77 to 1.61)	1.70
Pooled results for CIN2+ associated with HPV16/18 (FUTURE II trial (ph3,4v) and PATRICIA trial (ph3,2v)*******
DNA(‐)	Sero‐	5/14,014	120/13,372	0.03 (0.02 to 0.09)	5.85 (0.53 to 65.10)
DNA(‐)	Sero+	3/2205	14/2301	0.19 (0.09 t0 o.77)	5.85 (0.53 to 65.10)
DNA(+)	Sero‐	53/679	64/695	0.79 (0.60 to 1.05	1.37 (0.97 to 1.93)
DNA(+)	Sero+	100/531	96/639	1.10 (0.88 to 1.36)	1.37 (0.97 to 1.93)

Outcome	No. of doses	Vaccine arm	Placebo arm	Relative Risk (95%CI)	P value for linear dose‐effect relation
12‐month persistent HPV16/18 infection in women being HPV16/18 negative at baseline	3	84/11,104	627/11,203	0.135 (0.108 to 0.169)	0.303
	2	3/611	26/574	0.108 (0.033 to 0.356)
	1	1/292	17/249	0.050 (0.007 to 0.374)
6‐month persistent HPV16/18 infection in women being HPV16/18 negative at baseline	3	114/11,104	1000/11,209	0.115 (0.095 to 0.139)	0.269
	2	4/611	35/574	0.107 (0.038 to 0.300)
	1	1/292	24/250	0.036 (0.005 to 0.261)
Incident HPV16/18 infection in women being HPV16/18 negative at baseline	3	529/11,110	2172/11,217	0.246 (0.224 to 0.269)	0.337
	2	22/611	82/574	0.252 (0.160 to 0.398)
	1	8/292	45/251	0.153 (0.073 to 0.318)
12‐month persistent HPV16/18 infection in women being hrHPV negative at baseline	3	27/6634	351/6656	0.077 (0.052 to 0.114)	0.996
	2	2/273	12/276	0.168 (0.038 to 0.746)
	1	0/138	5/99	0.071 (0.004 to 1.289)
6‐month persistent HPV16/18 infection in women being hrHPV negative at baseline	3	38/6634	567/6660	0.067 (0.049 to 0.093)	0.809
	2	2/273	16/276	0.126 (0.029 to 0.544)
	1	0/138	8/100	0.045 (0.003 to 0.774)
Incident HPV16/18 infection in women being hrHPV negative at baseline	3	38/6634	567/6660	0.067 (0.049 to 0.093)	0.809
	2	2/273	16/276	0.126 (0.029 to 0.544)
	1	0/138	8/100	0.045 (0.003 to 0.774)

Outcome	No. of doses	n events	N vaccinated	% (95%CI)	*P for difference with 3 doses**
Cumulative incidence HPV16/18 infections	3	88	2023	4.3 (3.5 to 5.3)	‐
	2 (at months 0 & 6)	3	78	3.8 (1.0 to 10.1)	1.00
	2 (at months 0 & 1)	7	192	3.6 (1.6 to 7.1)	0.85
	1	2	133	1.5 (0.3 to 4.9)	0.17

Outcomes	Study	Report (duration of follow‐up)	Vaccine	Placebo	Relative Risk (95%CI)	P value for linear difference of follow‐up time effect
CIN2+ associated with HPV16/18 in women being HPV negative at baseline	PATRICIA	Paavonen 2007 14.8 moths	2/7788	21/7838	0.096 (0.007 to 0.466)	0.512
		Paavonen 2009 34.9 months	5/8040	91/8080	0.054 (0.016 to 0.137)
		Szarewski 2011 39.4 months	5/8079	92/8112	0.054 (0.016 to 0.137)
		Lehtinen 2011 43.7 months	5/7338	97/7305	0.051 (0.016 to 0.123)
	FUTURE	The FUTURE II study group 2007 36 months	3/5865	87/5836	0.039 (0.011 to 0.109)	0.994
	FUTURE	Munoz 2010* 43 months	0/4616	89/4680	0.006 (0.000 to 0.092)	0.994
CIN2+ irrespective of HPV types regardless of women’s initial HPV DNA status	PATRICIA	Paavonen 2009 34.9 months	224/8667	322/8682	0.696 (0.579 to 0.8369)	0.750
	PATRICIA	Lehtinen 2011 43.7 months	287/8694	428/8708	0.669 (0.574 to 0.778)	0.750
	FUTURE	The FUTURE II study group 2007 36 months	281/6087	361/6080	0.780 (0.668 to 0.905)	0.665
	FUTURE	Munoz 2010 43 months	421/8562	520/8598	0.807 (0.690 to 0.943)	0.665

Outcome	Age	Event/NVaccine	Event/NPlacebo	Relative risk (95% CI)	Vaccine efficacy (95% CI)	P value for linear effect of age
In women with HPV16/18 DNA negative status at baseline cohort
Persistent HPV16/18 infection (6M)	26‐35	3/834	22/800	0.13 (0.04 to 0.44)	87% (56% to 96%)	0.532
	36‐45	3/816	12/809	0.25 (0.07 to 0.88)	75%(12% to 93%)
	46+	0/219	0/213	N.A.	N.A.
Regardless if women’s baseline HPV DNA status
Persistent HPV16/18 infection (6M)	26‐35	48/1221	78/1242	0.63 (0.44 to 0.89)	37% (11% to 56%)	0.177
	36‐45	19/1244	43/1228	0.44 (0.26 to 0.74)	56% (26% to 74%)
	46+	4/300	11/306	0.37 (0.12 to 1.15)	63% (‐15% to 88%)

Outcome	P value
Outcome	V1	V2	V3	V4	V5	V6	V7
Persistent HPV16/18 infection (6M), in women being baseline HPV16/18 negative 3 doses	0.70	0.60	np	np	0.90	np	0.42
Persistent HPV16/18 infection (6M), in women being baseline HPV16/18 negative at least 1 dose	0.56	0.56	np	np	np	np	np
Persistent HPV16/18 infection (12M), in women being baseline HPV16/18 negative 3 doses	0.94	0.94	np	np	np	np	0.73
Persistent HPV16/18 infection (12M), in women being baseline HPV16/18 negative at least 1 dose	0.67	0.67	np	np	np	np	np

Outcomes	Age Group (years)	Studies	RR if 3 doses (95% CI)	RR if 1‐2 doses (95% CI)
CIN2+ due to HPV16/18	15‐26	5 (FUTURE II trial (ph3,4v); Japanese trial (ph2,2v); PATRICIA trial (ph3,2v); Phase2 trial (ph2,1v); Chinese trial (ph3,2v)_young)	0.07 (0.03 to 0.14)*	0.10 (0.04 to 0.26)*
CIN2+ due to HPV16/18	24‐45	2 (FUTURE III trial (ph3,4v); VIVIANE trial (ph3,2v))	0.14 (0.03 to 0.79)*	0.98 (0.20 to 4.83)
CIN3+ due to HPV16/18	15‐26	1 (PATRICIA trial (ph3,2v))	0.20 (0.04 to 0.91)*	0.04 (0.01 to 0.74)*
Incident HPV16/18 infection	15‐26	3 (Japanese trial (ph2,2v); Phase2 trial (ph2,1v);Chinese trial (ph3,2v)_young)	0.20 (0.10 to 0.41)*	0.47 (0.26 to 0.84)*
6‐month persistent HPV16/18 infection	15‐26	2 (Japanese trial (ph2,2v);Chinese trial (ph3,2v)_young)	0.05 (0.01 to 0.27)*	0.12 (0.03 to 0.42)*
6‐month persistent HPV16/18 infection	24‐45	2 (FUTURE III trial (ph3,4v);VIVIANE trial (ph3,2v))	0.15 (0.09 to 0.27)*	0.34 (0.19 to 0.61)*
12‐month persistent HPV16/18 infection	15‐26	3 (Japanese trial (ph2,2v);CVT (ph3,2v); Chinese trial (ph3,2v)_young)	0.09 (0.05 to 0.19)*	0.13 (0.06 to 0.33)*

Number of sex partners	Vaccine	Placebo	Relative Risk (95% CI)	P value of number of sexual partners effect
In women being HPV16/18 DNA negative at baseline cohort
Virgin	1/566	17/615	0.064 (0.003 to 0.352)	0.7448
1 partner	3/904	27/915	0.112 (0.007 to 0.335)
2 partners	1/544	17/519	0.056 (0.003 to 0.309)
3+ partners	3/621	28/628	0.108 (0.026 to 0.321)
Regardless of women’s baseline HPV DNA status
Virgin	4/733	21/819	0.202 (0.059 to 0.551)	< 0.0001
1 partner	40/1237	83/1256	0.489 (0.333 to 0.711)
2 partners	38/777	81/753	0.455 (0.307 to 0.665)
3+ partners	71/940	116/911	0.593 (0.440 to 0.796)

Outcomes	Study	Number of participants	Study size	Vaccine	Placebo	Relative Risk (95%CI)	P value
CIN2+ associated with HPV16/18 in women being HPV16/18 negative at baseline	Phase2 trial (V1)	2392	S	0/126	8/127	0.062* (0.004 to 1.071)	0.598
	Phase2 trial (V2)	1113	S	0/219	3/212	0.161* (0.008 to 3.091)
	Japanese trial (ph2,2v)	1040	S	0/422	2/427	0.252* (0.012 to 5.241)
	PATRICIA trial (ph3,2v)	18,644	L	5/8040	91/8080	0.055 (0.022 to 0.136)
	FUTURE II trial (ph3, 4v)	12,167	L	3/5865	87/5863	0.034 (0.011 to 0.109)
	Chinese trial (ph3,2V)	6051	L	0/2543	4/2554	0.125 (0.001 to 8.681)
CIN2+ irrespective of HPV types and regardless of women’s initial HPV DNA status	FUTURE I/II trial (ph3,4v)	17,622	L	421/8562	520/8598	0.813 (0.718 to 0.921)	0.703
	PATRICIA trial (ph3,2v)	18,644	L	287/8694	428/8708	0.672 (0.582 to 0.778)
	Phase2 trial (v1)	2392	S	8/148	12/142	0.640 (0.269 to 1.568)

Analysis	Endpoint	Initial HPV status	Doses	Relative Risk
Monovalent vaccine (Rowhani‐Rahbar, 2009): 102 months of follow‐up
3.1	CIN2+ associated with HPV16	HPV16‐	3	0.00
3.2	CIN2+ associated with HPV16	HPV16‐	>= 1	0.00
3.3	CIN2+ associated with HPV16	HPV16‐	1‐2	0.00
4.1	Incident HPV16 infection	HPV16‐	3	0.05
4.3	Incident HPV16 infection	HPV16‐	>= 1	0.11
4.3	Incident HPV16 infection	HPV16‐	1‐2	0.25
5.1	CIN2+ associated with HPV16	regardless of HPV infection	>= 1	0.36
5.3	CIN2+ irrespective of HPV types	regardless of HPV infection	>= 1	0.64
Bivalent vaccine (De Calvaho, 2012): 88 months of follow‐up
2.2	6M persistent HPV16/18 infection	hrHPV‐	3	0.00
2.4	12M persistent HPV16/18 infection	hrHPV‐	3	0.00
3.2	CIN2+ associated with HPV16/18	HPV16/18‐	>= 1	0.00
Quadrivalent vaccine (Villa, 2006): 60 months of follow‐up
4.8	Persistent HPV6/11/16/18 infection	HPV16/18‐	>= 1	0.07

Trials	Ref	Endpoint	Relative Risk (95% CI)		P value for difference in VE
Trials	Ref	Endpoint	Bivalent	Quadrivalent	P value for difference in VE
FUT I/II trials (ph3,4v)	Malagon 2012	6‐month persistent HPV31 infection	0.229 (0.156 to 0.228)	0.538 (0.336 to 0.847)	0.003
PATRICIA trial (ph3,2v)		6‐month persistent HPV45 infection	0.210 (0.106 to 0.387)	0.922 (0.507 to 1.670)	0.0003
Phase2 trial (ph2,2v)		CIN2+ associated with HPV33	0.177 (0.053 to 0.466)	0.760 (0.328 to 1.712)	0.02
Phase2 trial (ph2,4v)		CIN2+ associated with HPV45	0.000 (0.000 to 0.583)	0.481 (0.174 to 1.177)	0.04
CVT (ph3,2v)	Hildesheim 2014	CIN2+ associated with other hrHPV	0.401 (0.192 to 0.793)
VIVIANE trial (ph3,2v)	Skinner 2014	6‐month persistent HPV31 infection	0.209 (0.041 to 0.724)
VIVIANE trial (ph3,2v)	Skinner 2014	6‐month persistent HPV45 infection	0.221 (0.044 to 0.914)

Adverse effect		Relative risk	Relative risk ratio	p value
Adverse effect		Quadrivalent vs placebo	Bivalent/Quadrivalent	p value
1	Overall adverse effects at injection site	1.19 (0.89 to 1.59)	1.69 (0.96 to 2.96)	0.061
2	Pain at injection site	1.20 (0.78 to 1.85)	1.19 (0.67 to 2.12)	0.501
3	Swelling at injection site	2.72 (0.77to 9.61)	0.62 (0.16 to 2.41)	0.427
4	Redness at injection site	1.46 (1.23 to 1.74)	1.08 (0.88 to 1.32)	0.307
5	Overall systemic events	0.99 (0.91 to 1.07)	1.06 (0.95 to 1.19)	0.210
6	Serious adverse events	0.94 (0.70 to 1.26)	1.08 (0.80 to 1.45)	0.583
7	Deaths	1.18 (0.25 to 5.62)	0.84 (0.14 to 4.91)	0.775

	Monovalent vaccine	Bivalent vaccine	Quadrivalent vaccine
Manufacturer	Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)	GlaxoSmithKline (GSK, Rixensart, Belgium)	Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)
Antigens	HPV16 (40 μg)	L1 VLPs of HPV16 (20 μg) and HPV18 (20 μg)	L1 VLPs of HPV6 (20 μg), HPV11 (40 μg), HPV16 (40 μg) and HPV18 (20 mg)
Vaccination schedule	3 doses: at day 1, month 2 and month 6	3 doses: at day 1, month 1 and month 6	3 doses: at day 1, month 2 and month 6
Adjuvant	225 μg amorphous aluminium hydroxyl‐phosphate sulphate	AS04: 500 μg aluminium hydroxide, 50 μg 3‐deacylated monophosphoryl lipid A (MPL)	225 μg amorphous aluminium hydroxyl‐phosphate sulphate
Trade name	Not commercialised	Cervarix	Gardasil, Silgard
Produced by recombinant technology using	Saccharomyces cerevisae (baker’s yeast)	Baculovirus in Trichoplusia in insect cells	Saccharomyces cerevisae (baker’s yeast)

	Nona‐valent vaccine (Luxembourg 2015)
Manufacturer	Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)
Antigens	L1 VLPs of HPV6 (30 μg), HPV11 (40 μg), HPV16 (60 μg), HPV18 (40 mg), HPV31 (20 μg), HPV33 (20 μg), HPV45 (20 μg), HPV52 (20 μg) and HPV58 (20 μg).
Vaccination schedule	3 doses: at day 1, month 2 and month 6
Adjuvant	500 μg amorphous aluminium hydroxyl‐phosphate sulphate
Trade name	Gardasil‐9
Produced by recombinant technology using	Saccharomyces cerevisae (baker’s yeast)

PERMALINK

Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors

Marc Arbyn

Lan Xu

Cindy Simoens

Pierre PL Martin‐Hirsch

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Burden of cervical cancer

Association between human papillomavirus (HPV) infection and cervical cancer and other HPV‐related cancers and their precursors

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Intervention

Comparison

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Registries of randomised trials

International public health organisations

Handsearching

Correspondence

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

1. Listing of included trials.

Excluded studies

Risk of bias in included studies

2.

3.

4.

Effects of interventions

Summary of findings for the main comparison. HPV vaccine effects on cervical lesions in adolescent girls and women negative for hrHPV DNA at baseline.

Summary of findings 2. HPV vaccine effects on cervical lesions in adolescent girls and women negative for HPV16/18 DNA at baseline.

Summary of findings 3. HPV vaccine effects in adolescent girls and women regardless of HPV DNA status at baseline.

Summary of findings 4. HPV vaccine effects on pregnancy outcomes.

2. Results of all the efficacy outcomes.

1. Protection against high‐grade cervical lesions in women negative for hrHPV DNA at baseline

1.1. Analysis.

1.3. Analysis.

1.5. Analysis.

1.2. Analysis.

1.4. Analysis.

1.6. Analysis.

1.7. Analysis.

1.8. Analysis.

1.9. Analysis.

No.	ID Internal	ID NCT	ID Cochrane	Publications	Phase	Countries/ continents	Age	Number	Reason exclusion	Safety	Efficacy
1. Bivalent vaccine
1.1. Published reports included in the Cochrane review
1	HPV‐001	NCT00689741	Phase 2 trial (v2)	Harper 2004 Harper 2006 De Carvalho 2010	IIb	Brazil, Canada, USA	16‐25y	1113	‐	+	+
2	HPV‐008	NCT00122681	PATRICIA	Paavonen 2007 Paavonen 2009 Wacholder 2010 Szarewski 2011 Wheeler 2011 Lehtinen 2012	III	America, Asia, Europe, Oceania	15‐25y	18,644	‐	+	+
3	HPV‐009	NCT00128661	CVT	Herrero 2011	III	Costa Rica	18‐25y	7466	‐	+	+
4	HPV‐013	NCT00196924 NCT00316706	immuno‐bridging (ph3,2v)	Medina 2010 Schwarz 2012	III	America, Asia, Europe, Oceania	10‐14y	2067	‐	+	_
5	HPV‐015	NCT00294047	VIVIANE	Skinner 2014	III	Europe	≥26y	5752	‐	+	+
6	HPV‐021	NCT00481767	African_2 country trial (ph3,2v)	Sow 2013	III	Africa	10‐25y	676	‐	+	‐
7	HPV‐031	NCT00344032	India trial (ph3,2v)	Bhatla 2010	III	India	18‐35y	354	‐	+	‐
8	HPV‐032	NCT00316693	Japanese trial(ph2, 2v)	Konno 2010 Konno 2010a Konno 2014	II	Japan	20‐25y	1046	‐	+	‐
9	HPV‐033	NCT00290277	Korean trial (ph3b,2v)	Kim 2010	III	Korea	10‐14y	321	‐	+	‐
10	HPV‐035	NCT00306241 NCT00811798	Hong Kong trial (ph3,2v)	Ngan 2010	III	Hong Kong	18‐35y	300	‐	+	‐
11	HPV‐036	NCT00345878	Malaysian trial (ph3,2v)	Lim 2014	III	Malaysia	18‐35y	271	‐	+	‐
12	HPV‐038	NCT00485732	Korean trial (ph3,2v)	Kim 2011	III	S‐Korea	15‐25y	225	‐	+	‐
13	HPV‐058	NCT00996125	Chinese trial (ph3,2v)_adolescent	Zhu 2014a	III	China	9‐17y	750	‐	+	‐
14	HPV‐039	NCT00779766	Chinese trial (ph3,2v)_young	Zhu 2014	III	China	18‐25y	6051	‐	+	+
15	HPV‐069	NCT01277042	Chinese trial (ph3,2v)_mid‐adult	Zhu 2014a	III	China	26‐45y	1212	‐	+	‐
1.2. Excluded studies
16	HPV‐020	NCT00586339	‐	Denny 2013	II	S‐Africa	18‐25y	150	HIV sero+ women: randomised to vaccine or placebo. Small group HIV sero‐ women: all received vaccine.	+	‐

1.3. Non published studies*
17	HPV‐003	NCT00263744	‐	‐	I/II	USA	18‐30y	60	Trial evaluating safety and immunogenicity in HPV16/18 DNA positive women. No data published	+	‐
18	HPV‐004	NCT00693615	‐	‐	II	USA	18‐30y	60	All randomised women received the HPV vaccine with ASO4 adjuvants, aluminium adjuvants or no adjuvants. There was no placebo control group who did not receive the bivalent vaccine.	+	‐
19	HPV‐005	NCT00693966	‐	‐	II	USA	18‐30y	210	Dose escalating trial without placebo group. There was no placebo control group who did not receive the bivalent vaccine.	+	‐
20	HPV‐012	NCT00169494	‐	‐	III	Europe	10‐25y	770	Trial evaluating lot‐to‐lot consistency and consistency with new manufacturing process.There was no placebo control group who did not receive the bivalent vaccine.	+	‐
										+	‐
									Total 1.1.‐1.3.	47,498
									In Cochrane review (1.1)	46,248	97.4%
									Not included in Cochrane review (1.2 + 1.3)	1,250	2.6%
1.4. Sub‐studies already included
21	HPV‐007 (HPV‐001 FU‐extension)	NCT00120848	Phase 2 trial (v2)	Romanowski 2009	IIb	Brazil, Canada, USA	15‐25y	776	‐	+	+
22	‐	NCT00456807	‐	‐	III	Netherlands	≥26y	100	Sub‐study of HPV‐015 investigating additional immunogenicity parameters in an included study.	+	‐

2.Quadrivalent vaccine
2.1. Published reports included in the Cochrane review
23	V501‐005	NCT00365378	Phase2 trial (1v)	Koutsky 2002 Mao 2006 Rowhani‐Rahbar 2009	II	USA	16‐23y	2392	‐	+	+
24	V501‐007	NCT00365716	Phase 2 trial (4v)	Villa 2005 Villa 2006 Villa 2006a	II	America, Europe	16‐23y	1158	‐	+	+
25	V501‐013	NCT00092521	Future I trial	Garland 2007	III	Asia‐Pacific, America, Europe	16‐24y	5455	‐	+	+
26	V501‐015	NCT00092534	FUTURE II trial	FUTURE‐II 2007	III	America, Asia, Europe	15‐26y	12,167	‐	+	+
27	V501‐019	NCT00090220	FUTURE III trial	Munoz 2009 Castellsagué 2011	III	America, Asia, Europe	24‐45y	3819	‐	+	+
28	V501‐023	NCT00157950	Korean trial (ph2,4v)	Kang 2008	III	Korea	9‐15y 16‐23y	176	‐	+	‐
29	V501‐027	NCT00378560	Japanese trial (ph2,4v)	Yoshikawa 2013	II	Japan	18‐26y	1021	‐	+	+
30	V501‐046	NCT01245764	African_3 country trial (ph3, 4v)	Mugo 2015	III	Ghana, Kenya, Senegal	Females 9‐26y	250	‐	+	‐
2.2. Excluded studies
31	V501‐018	NCT00092547	‐	Reisinger 2007	III	America, Europe Asia	Girls 9‐15y	939	Study included also male participants. Data could not be separated by gender.	+	‐
32	V501‐030	NCT00496626	‐	Li 2012	III	China	Females 9‐45y	400	Study included also male participants. Data could not be separated by gender. Request for data for female participants only was not answered	+	‐

2.3. Non published reports
									Total 2.1.‐2.3.	27,777
									Included in Cochrane review (2.1)	26,438	95.2%
									Not included in Cochrane review (2.2 + 2.3)	1339	4.8%
4. Sub‐studies already included
33	V501‐011	NCT00517309	FUTURE I trial sub	Wheeler 2008	III	Asia‐Pacific, America, Europe	16‐23 yrs	1877	‐	+	+
34	V501‐012	NCT00092482	FUTURE I sub	Garland 2007a	III	Asia‐Pacific, America, Europe	16‐23 yrs	3882	‐	+	+

Study	Location	Recruitment period	Valency of the vaccine	Placebo	Endpoints	Follow‐up schedule
Phase2 trial (ph2,1v)	US	Oct98‐Nov99	Monovalent	225 µg amorphous aluminium hydroxyl‐phosphate sulphate	Persistent infection; CIN 1,2 & 3; Immunogenicity ; Adverse effects	7 M,every 6 M until 48 M; cytology & HPV DNA testing
Japanese trial (ph2,2v)	Japan	Apr06‐Oct06	Bivalent	Hepatitis A Vaccine	Persistent infection (6 &12 M); Cytological abnormality and CIN; Safety; Immunogenicity	Cytology and HPV DNA test at M 0,6,12,18 and 24.
Phase2 trial (ph2,2v)	Brazil, US, Canada	Jul02‐Dec02	Bivalent	500 µg aluminium hydroxide	Incident infection and persistent infection(6 & 12 M) ; LSIL+, ASCUS+ and HSIL+; CIN1+, CIN2+; Immunogenecity; Safety & tolerability	Brush/spatula smears at 6,12,18 M by provider; Cervicovaginal self‐samples at 0 & 6 M; subsequently every 3 M until 27 M
African_2 country trial (ph3,2v)	Senegal Tanzania	Oct07‐Jul10	Bivalent	500 μg aluminium hydroxide	Adverse events; Immunogenicity	/
Chinese trial (ph3,2v)_young	China	Oct08‐Apr11	Bivalent	50 μg MPL and 500 μg aluminium hydroxide	Incident infection and persistent infection (6 M &12 M); Adverse events; Immunogenicity	/
Chinese trial (ph3,2v)_ adolescent	China	Oct09‐Nov12	Bivalent	50 μg MPL and 500 μg aluminium hydroxide	Adverse events; Immunogenicity	/
Chinese trial (ph3,2v)_mid‐adult	China	Jan11‐Oct14	Bivalent	Hepatitis B Vaccine	Adverse events; Immunogenicity	/
Co‐vaccination_dTpa_IPV trial (ph3,2v)	France, Germany and Spain	Feb07‐Mar08	Bivalent	Combined Diphtheria‐Tetanus‐Acellular Pertussis–inactivated Poliovirus vaccine.	Adverse events; Immunogenicity	/
Co‐vaccination_HAB trial (Ph3, 2v)	Canada, Denmark, Hungary and Sweden	Dec07‐Dec08	Bivalent	GSK combined hepatitis A and B vaccine	Adverse events; Immunogenicity	/
Co‐vaccination_HepB trial (ph3, 2v)	Nederlands and Sweden	Apr08‐Jan10	Bivalent	Hepatitis B vaccine	Adverse events; Immunogenicity	/
CVT (ph3,2v)	Costa Rica	Jun04‐Dec05	Bivalent	Hepatitis A Vaccine	HPV16/18 persistent infection (6 &12 M); Cross‐protection; Adverse events	Cytology examinations every 12 M; If LSIL or HPV+ASCUS, then check for every 6 M.
Hong Kong trial (ph3,2v)	Hong Kong	Mar06‐Jun07	Bivalent	500 μg aluminium hydroxide	Adverse events; Immunogenicity	/
Immunobridging(ph3,2v)	Australia, Colombia, the Czech Republic, France, Germany, Honduras, Korea, Norway, Panama, Spain, Sweden and Taiwan	Jun04‐Aug05	Bivalent	Hepatitis A Vaccine	Adverse events; Immunogenicity	/
Indian trial (ph3,2v)	India	Jul06‐Mar07	Bivalent	500 μg aluminium hydroxide	Adverse events; Immunogenicity	/
Korean trial (ph3,2v)	Korea	Nov05‐Aug06	Bivalent	Hepatitis A vaccine	Adverse events; Immunogenicity	/
Korean trial (ph3b,2v)	Korea	Jun07‐Mar08	Bivalent	500 μg aluminium hydroxide	Adverse events; Immunogenicity	/
Malaysian trial (ph3,2v)	Malaysia	Sep06‐Dec07	Bivalent	500 μg aluminium hydroxide	Adverse effects, immunogenicity	/
PATRICIA trial (ph3,2v)	15 countries in all continents but Africa	May04‐Jun05	Bivalent	Hepatitis A Vaccine	CIN2+; Persistent infection ( 6 &12 M); CIN1+; Immunogenecity; Adverse events	Cervical samples for HPV genotyping, every 6 M. Gynaecological and cytology examinations every 12 M.
VIVIANE trial (ph3,2v)	12 countries in all continents but Africa	Feb06‐Dec10	Bivalent	500 μg aluminium hydroxide	Combined endpoints of persistent infection (6 M) or CIN1+; Immunogenicity; Adverse events	Cytology sample for HPV DNA testing every 6 M and Pap smear every 12 M; If ASC‐US+, then refer to colposcopy immediately.
Japanese trial (ph2,4v)	Japan	Not mentioned	Quadrivalent	225 µg amorphous aluminium hydroxyl‐phosphate sulphate	Composite primary endpoint of persistent infection; cervical and external genital disease	Gynecological examination was done at day 1 and at months 7,12,18,24 and 30. A ThinPrep Pap test and external genital and cervical swabs for PCR analysis of HPV were obtained from all participants at day 1 and at months 7,12,18,24 and 30. Biopsy samples of external genital lesions identified during the study were taken and serum samples were obtained at day 1 and months 2,3,7,18 and 30.
Korean trial (ph2,4v)	South Korea	Oct05‐May06	Quadrivalent	225 µg aluminium adjuvant of safety comparisons 0.5 mL	Adverse events; Immunogenicity	/
Phase2 trial (ph2,4v)	Brazil, Europe, US	May00‐May04	Quadrivalent	225 µg or 450 µg amorphous aluminium hydroxyl‐phosphate sulphate	HPV6/11/16/18 persistent infection (>=4 M); VIN, VaIN or GW; Immunogenecity; Safety &tolerability	‐ Gynaecological examination at 0,7,12M, subsequently every 6 M until 36 M: ‐ ThinPrep smear; swabs: cervix, vaginal, external genital for HPV PCR ‐ Biopsies from external genital lesions ‐ Serum at 0,2,3,7,12,18,24,36 M
African_3 country trial (ph3,4v)	Ghana, Kenya, and Senegal	/	Quadrivalent	225 µg amorphous aluminium hydroxyl‐phosphate sulphate	Adverse events; Immunogenicity	/
FUTURE I trial (ph3,4v)	16 countries in Asia‐Pacific, North America, Latin America and Europe	Dec01‐Aug08	Quadrivalent	225 µg amorphous aluminium hydroxyl‐phosphate sulphate	CIN of any grade, AIS or Cervical Cancer; Incidence of GW, VIN and VaIN; Adverse events	Gynecologic examination at day 1, M 7, 12, 24, 36 and 48; Comprehensive anogenital examination at day 1, M 3, M 7, 12, 18, 24, 30, 36 and 48; Day1, M 7,12,18, 24, 30, 36, 48 ThinPrep Cytology;
FUTURE II trial (ph3,4v)	13 countries in Asia‐Pacific, North America, Latin America and Europe	Jun02‐May03	Quadrivalent	225 µg amorphous aluminium hydroxyl‐phosphate sulphate	CIN2, CIN3, AIS and cervical cancer; Adverse events	Gynecologic examination, comprehensive anogenital examination and cytology at day 1, follow up at M 7, 12, 24, 36 and 48
FUTURE III trial (ph3,4v)	7 countries in all continents but Africa	Jun04‐Apr05	Quadrivalent	225 µg amorphous aluminium hydroxyl‐phosphate sulphate	CIN1‐3,VIN1‐3, VaIN1‐3,AIS, cervical, vaginal and vulvar cancer; Persistent infection (6 M); Genital wart	Pelvic examination, inspection with loupe, labial, vulval, perineal, perianal,endo & ectocervical swabs at M 0,7, 12, 18, 24, 30, 36, 42, 48.

Study	HPV DNA detection methods	HPV serology method	Definition of per‐protocol population	Definition of intention‐to‐ treat population
Phase2 trial (ph2,1v)	PCR targeting L1, E6 and E7 genes of HPV16.	Competitive radioimmunoassay(cLIA) to detect HPV16 antibodies (Merck Research Laboratories). Cut‐off for sero+ 5.9 mMU/mL At enrolment also an ELISA test was used. At M 7,12,18, 30, 42.	Women who had 3 doses. Seronegative for HPV‐16 and negative for HPV‐16 DNA at day 0, and HPV‐16 DNA negative at M 7. No sexual intercourse within 48 hours before day 0 and M 7 visit. No other non‐study vaccine, no other drugs or involved in other studies.	Efficacy analysis including women with general protocol violations: had 3 doses, seronegative for HPV16 and negative for HPV16 DNA on day 0 and negative for HPV16 DNA at M 7 and in any biopsy specimens obtained between day 0 and M 7.
Japanese trial (ph2,2v)	SPF10 PCR (HPV LiPA‐version 1), to identify 14 hrHPV types (16, 18, 31, 33, 35, 39, 45, 51,52, 56, 58, 59, 66, 68). If sample negative for HPV16 or 18, type‐specific PCR for HPV16 or 18 was performed.	/	Meet eligibility criteria, complied with protocol procedures, received 3 doses and were DNA negative of corresponding HPV types at M 0 and 6, had efficacy endpoints measures available, had no or low‐grade cytological abnormality at M0, and were seronegative for the corresponding HPV type at M 0.	/
Phase2 trial (ph2,2v)	PCR SPF10 primers Typing with DNA immunoenzyme assay (LiPA [Innogenetics, Gent] If LiPA+: type specific PCR: HPV16 (E6/7), HPV18 (L1)	ELISA test using HPV16 & HPV18 VLP as antigen.	Women who have received the 3 scheduled doses and complied with the protocol and were not excluded. ‐ evaluation of safety: 540 versus 541 ‐ evaluation of efficacy: 366 versus 355 (initially seropositive, HPV DNA positive & cytologically positive women are excluded) ‐ evaluation of immunogenicity: 384 vs 344: women with serology results at months 0, 7 and 18, who received all 3 doses, and did not become positive for HPV16/18 DNA during administration period.	Women who had received at least one dose of study vaccine or placebo in the initial efficacy study, and who had any data available for outcome measurement in the extended follow‐up phase. For efficacy study, women who were HPV DNA negative for the specific HPV type at month 0 in the initial study also included.
African_2 country trial (ph3,2v)	/	ELISA	ATP for immunogenicity, which  included evaluable participants meeting all eligibility criteria,  complying with the procedures and intervals defined in the  protocol (including receipt of the scheduled number of doses),  with no elimination criteria during the trial, for whom immunogenicity  data were available.	TVC included all participants with at least one vaccine/placebo dose administration documented.
Chinese trial (ph3,2v)_young	PCR SPF10‐DEIA‐LiPA25 version 1 test for HPV16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.	ELISA	ATP‐E included women who were seronegative at M 0 and DNA negative at M 0 and 6, received all 3 doses and had normal or low‐grade cytology at baseline.	TVC‐E included all vaccinated women for whom efficacy data were available and who had normal or low‐grade cytology at baseline. Included women were seronegative at M 0 and HPV negative at M 0 and 6.
Chinese trial (ph3,2v)_ adolescent	/	ELISA	ATP for immunogenicity included women who met eligibility criteria and were seronegative at M 0.	TVC included all participants with at least one vaccine/placebo dose administration documented.
Chinese trial (ph3,2v)_mid‐adult	/	ELISA	ATP for immunogenicity included women who met eligibility criteria and were seronegative at M 0.	TVC included all participants with at least one vaccine/placebo dose administration documented.
Co‐vaccination_dTpa_IPV trial (ph3,2v)	/	ELISA	ATP for immunogenicity included women who met eligibility criteria and were seronegative at M 0.	TVC included all participants with at least one vaccine/placebo dose administration documented.
Co‐vaccination_HAB trial (Ph3, 2v)	/	ELISA	ATP for immunogenicity included women who met eligibility criteria and were seronegative at M 0.	TVC included all participants with at least one vaccine/placebo dose administration documented.
Co‐vaccination_HepB trial (ph3, 2v)	/	ELISA	ATP for immunogenicity included women who met eligibility criteria and were seronegative at M 0.	TVC included all participants with at least one vaccine/placebo dose administration documented.
CVT (ph3,2v)	Broad‐spectrum PCR‐based HPV DNA test, use SPF10 (HPV‐LiPA‐version 1) to ensure HPV16 and HPV18 infections detection.	ELISA used for the detection and quantification of IgG antibodies against HPV16 and 18 separately.	ATP: no protocol violations, received all 3 doses within protocol‐defined period, had no biopsy/treatment before the 6‐month visit, and were HPV DNA‐negative by PCR for the corresponding HPV type at enrolment and the 6‐month visit.	ITT: All randomised women, regardless of compliance or enrolment infection.
Hong Kong trial (ph3,2v)	/	ELISA with cut‐off 8 EL.U/mL for HPV16 and 7 EL.U/mL for HPV 18.	ATP included participants who met eligibility criteria, complied with protocol‐defined procedures, and for whom post‐vaccination assay results were available for antibodies against at least one study vaccine antigen.	TVC included participants who received at least one dose of the vaccine.
Immunobridging(ph3,2v)	/	ELISA	ATP:included participants who met all eligibility criteria, complied with study procedures,and had data available for antibodies against at least 1 antigen component of the bivalent vaccine.	All participants who completed the study without considering protocol violation.
Indian trial (ph3,2v)	/	ELISA with cut‐off 8 EL.U/mL for HPV16 and 7 EL.U/mL for HPV 18.	ATP included all subjects meeting eligibility criteria, complying with the procedures defined in the protocol and for whom assay results were available fro antibodies against at least one study vaccine antigen component after vaccination.	TVC included all subjects with at least one vaccine/placebo dose administration documented.
Korean trial (ph3,2v)	/	ELISA	ATP cohort including all participants meeting eligibility criteria, complying with the procedures defined in the protocol, and for whom assay results were available for antibodies against at least one study antigen component after vaccination.	TVC included all participants with at least one vaccine/placebo dose administration documented.
Korean trial (ph3b,2v)	/	ELISA	ATP: included all eligible participants (those meeting all eligibility criteria, complying with protocol defined procedures, without elimination criteria during the study) for whom immunogenicity data were available.	With at least one dose of vaccine administrated
Malaysian trial (ph3,2v)	/	ELISA with cut‐off 8 EL.U/mL for HPV16 and 7 EL.U/mL for HPV18.	ATP: all evaluable participants (those meeting all eligibility criteria, complying with protocol defined procedures, without  elimination code during the study) for whom immunogenicity data were available.	TVC: all participants with at least one documented vaccine dose administration.
PATRICIA trial (ph3,2v)	SPF10 PCR (HPV LiPA‐version 1), to identify 14 hrHPV types (16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). If multiple infection, causality was attributed to the type also present in a previous cervical sample.	Serology HPV16/18 (ELISA) at M 0,7, 24 for all and at M 6, 12, 36, 48 at selected sites.	ATP‐Efficacy: no protocol violations, received 3 doses, NILM, ASC‐US or LSIL at baseline, evaluable for efficacy, case counting after the 3^rd dose; ATP‐Immunogenicity cohort: no protocol violations, received 3 doses, included in sites for study of immunogenicity.	TVC: at least 1 dose received, baseline HPV/cyto exam and at least 1 FU examination (all HPV/cyto+ at baseline included). TVC‐E: idem but HSIL and unknown cyto at baseline excluded. TVC‐N: idem as TVC, but baseline NILM, hrHPV DNA‐ (14 types, M 0 & M 7?) and sero‐ for HPV16/18 (M 0).
VIVIANE trial (ph3,2v)	Broad‐spectrum PCR SPF10‐DEIA‐LiPA test for HPV16, 18 ,31 ,33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68/73. Oncogenic HPV‐positive women were tested by multiplex type‐specific PCR and reverse hybridisation assay (MPTS12) to detect HPV16,18, 31,33, 35, 45, 52, 58,and 59.	ELISA used to detect antibody response against HPV16 and 18 at 6M intervals up to 24M and at 12M intervals thereafter.	ATP‐E: no protocol violations, received all 3 doses, data for efficacy endpoints available (baseline PCR or cytology sample and one further sample available); negative or low‐grade cytology at M 0, no history of HPV disease; counting of events after 3rd dose.	TVC: at least 1 dose; data available for efficacy endpoints; HSIL excluded; include participants of women with history of HPV disease (15%); case counting after first dose; Endpoint assessed irrespective of baseline HPV DNA or serostatus; TVC‐E: all the same except that endpoint assessed in women DNA negative and seronegative for corresponding HPV type at month 0.
Japanese trial (ph2,4v)	/	Competitive immunoassay (cLIA, Luminex Crp, Austin,TX,US)	Per‐protocol: women who were naive for the relevant HPV type at enrolment, remained free of infection with the same vaccine HPV type through completion of the vaccination regimen, had 3 doses, no protocol violations. Cases counting start form M 7.	/
Korean trial (ph2,4v)	/	Competitive immunoassay (cLIA, Luminex Crp, Austin,TX,US	Per‐protocol: received all 3‐doses, meet all the eligibility of inclusion, complying with all the protocol procedures	With at least one dose of vaccine administrated
Phase2 trial (ph2,4v)	Type specific PCR for HPV6/11/ 16/18. HC2 triage for ASCUS cases.	Competitive immunoassay (cLIA, Luminex Crp, Austin,TX,US)	Naïve for relevant HPV types at enrolment, still free of infection with HPV types 1 month after completion of vaccination regimen of 3 doses within 1 year, who did not violate protocol (N = 431 for HPV6/11, 404 for HPV16, 456 for HPV18). Cases are counted from M 7.	Naïve to the relevant HPV type (S) at enrolment and had received at least one dose. Protocol violators were included.
African_3 country trial (ph3,4v)	/	Competitive immunoassay (cLIA, Luminex Crp, Austin,TX,US)	ATP for immunogenicity included women who met eligibility criteria and were seronegative at M 0.	TVC included all participants with at least one vaccine/placebo dose administration documented.
FUTURE I trial (ph3,4v)	Type specific PCR for HPV6/11/ 16/18.	Competitive immunoassay (cLIA, Luminex Crp, Austin,TX,US)	Per‐protocol: received all 3 doses within 12M, seronegative and HPV DNA negative for vaccine type from day 1 till 1 month after the 3^rd does, remained HPV negative; no protocol violations, include even the first day cytology were abnormal	ITT: included even if they had infection or disease associated with vaccine type before vaccination; protocol violations were present; or results on cervical cytological examination at day 1 were abnormal.
FUTURE II trial (ph3,4v)	Type specific PCR for HPV6/11/ 16/18.	Competitive immunoassay (cLIA, Luminex Crp, Austin,TX,US)	Per‐protocol: received all 3 doses within 12 M, seronegative and HPV DNA negative for vaccine type understudy from day1 till M 7. Have 1 or more follow‐up visit S after M 7. No protocol violations.	/
FUTURE III trial (ph3,4v)	Type specific multiplex PCR for HPV6/11/ 16/18 targeting L1,E6,E7 genes.	Competitive immunoassay (cLIA, Luminex Crp, Austin,TX,US) at month 0,7, 12, 24, 36, 48.	Seronegative for relevant type at day 1, PCR negative for that type in cervicovaginal samples at day 0 and M 7; all 3 doses received within 1 year with 1 or more follow‐up visits after 7 M.	Women who received at least one dose of vaccine or placebo and had one or more follow‐up visits after day 1. Both protocol violators and those with pre‐existing HPV infections were included in ITT analyses. Cases were counted starting at day 1.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CIN2+ associated with HPV16/18, at least 1 dose	3	23676	Risk Ratio (IV, Random, 95% CI)	0.01 [0.00, 0.05]
2 CIN2+ associated with HPV6/11/16/18, at least 1 dose	1	9296	Risk Ratio (IV, Random, 95% CI)	0.01 [0.00, 0.09]
3 CIN3+ associated with HPV16/18, at least 1 dose	2	20214	Risk Ratio (IV, Random, 95% CI)	0.01 [0.00, 0.10]
4 CIN3+ associated with HPV6/11/16/18, at least 1 dose	1	9296	Risk Ratio (IV, Random, 95% CI)	0.01 [0.00, 0.18]
5 AIS associated with HPV16/18, at least 1 dose	2	20214	Risk Ratio (IV, Random, 95% CI)	0.10 [0.01, 0.82]
6 AIS associated with HPV6/11/16/18, at least 1 dose	1	9296	Risk Ratio (IV, Random, 95% CI)	0.14 [0.01, 2.80]
7 Any CIN2+ irrespective of HPV types, at least 1 dose	5	25180	Risk Ratio (IV, Random, 95% CI)	0.37 [0.25, 0.55]
7.1 Bivalent vaccine	4	15884	Risk Ratio (IV, Random, 95% CI)	0.33 [0.25, 0.43]
7.2 Quadrivalent vaccine	1	9296	Risk Ratio (IV, Random, 95% CI)	0.57 [0.44, 0.76]
8 Any CIN3+ irrespective of HPV types, at least 1 dose	3	20719	Risk Ratio (IV, Random, 95% CI)	0.21 [0.04, 1.10]
8.1 Bivalent vaccine	2	11423	Risk Ratio (IV, Random, 95% CI)	0.08 [0.03, 0.23]
8.2 Quadrivalent vaccine	1	9296	Risk Ratio (IV, Random, 95% CI)	0.54 [0.36, 0.82]
9 Any AIS irrespective of HPV types, at least 1 dose	2	20214	Risk Ratio (IV, Random, 95% CI)	0.10 [0.01, 0.76]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CIN2+ associated with HPV16/(18), 3 doses	8	43376	Risk Ratio (IV, Random, 95% CI)	0.08 [0.04, 0.16]
1.1 Age group 15‐26 years	6	36579	Risk Ratio (IV, Random, 95% CI)	0.07 [0.03, 0.15]
1.2 Age group 24‐45 years	2	6797	Risk Ratio (IV, Random, 95% CI)	0.16 [0.04, 0.74]
2 CIN2+ associated with HPV16/(18), at least 1 dose	8	42030	Risk Ratio (IV, Random, 95% CI)	0.10 [0.05, 0.20]
2.1 Age group 15‐26 years	6	34478	Risk Ratio (IV, Random, 95% CI)	0.05 [0.03, 0.10]
2.2 Age group 24‐45 years	2	7552	Risk Ratio (IV, Random, 95% CI)	0.30 [0.11, 0.81]
3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis)	7	3713	Risk Ratio (IV, Random, 95% CI)	0.19 [0.07, 0.51]
3.1 women age 15‐26 years	5	2958	Risk Ratio (IV, Random, 95% CI)	0.10 [0.04, 0.26]
3.2 women age 24‐45 years	2	755	Risk Ratio (IV, Random, 95% CI)	0.61 [0.14, 2.67]
4 CIN2+ associated with HPV6/11/16/18, 3 doses	2	7664	Risk Ratio (IV, Random, 95% CI)	0.06 [0.01, 0.61]
4.1 Age group 15‐26 years	1	4499	Risk Ratio (IV, Random, 95% CI)	0.02 [0.00, 0.25]
4.2 Age group 24‐45 years	1	3165	Risk Ratio (IV, Random, 95% CI)	0.17 [0.02, 1.39]
5 CIN2+ associated with HPV6/11/16/18, at least 1 dose	2	8980	Risk Ratio (IV, Random, 95% CI)	0.08 [0.00, 2.41]
5.1 Age group 15‐26 years	1	5351	Risk Ratio (IV, Random, 95% CI)	0.01 [0.00, 0.19]
5.2 Age group 24‐45 years	1	3629	Risk Ratio (IV, Random, 95% CI)	0.37 [0.10, 1.41]
6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis)	2	1316	Risk Ratio (IV, Random, 95% CI)	0.24 [0.01, 5.00]
6.1 Age group 15‐26 years	1	852	Risk Ratio (IV, Random, 95% CI)	0.04 [0.00, 0.74]
6.2 Age group 24‐45 years	1	464	Risk Ratio (IV, Random, 95% CI)	0.97 [0.14, 6.80]
7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses	3	29720	Risk Ratio (IV, Random, 95% CI)	0.07 [0.02, 0.29]
8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose	3	33199	Risk Ratio (IV, Random, 95% CI)	0.05 [0.02, 0.14]
9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis)	3	3479	Risk Ratio (IV, Random, 95% CI)	0.06 [0.01, 0.24]
10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses	3	29707	Risk Ratio (IV, Random, 95% CI)	0.12 [0.02, 0.70]
11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose	2	17079	Risk Ratio (IV, Random, 95% CI)	0.09 [0.01, 0.72]
12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis)	2	2015	Risk Ratio (IV, Random, 95% CI)	0.15 [0.01, 2.97]
13 Any CIN2+ irrespective of HPV types, 3 doses	3	7320	Risk Ratio (IV, Random, 95% CI)	0.40 [0.25, 0.64]
14 Any CIN2+ irrespective of HPV types, at least 1 dose	3	19143	Risk Ratio (IV, Random, 95% CI)	0.41 [0.32, 0.52]
15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis)	1	34	Risk Ratio (IV, Random, 95% CI)	0.71 [0.15, 3.38]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CIN2+ associated with HPV16/18, at least 1 dose	5	44052	Risk Ratio (IV, Random, 95% CI)	0.52 [0.41, 0.67]
1.1 Age group 15‐26 years	3	34852	Risk Ratio (IV, Random, 95% CI)	0.46 [0.37, 0.57]
1.2 Age group 24‐45 years	2	9200	Risk Ratio (IV, Random, 95% CI)	0.74 [0.52, 1.05]
2 CIN2+ associated with HPV6/11/16/18, at least 1 dose	2	20883	Risk Ratio (IV, Random, 95% CI)	0.57 [0.38, 0.86]
2.1 Age group 15‐26 years	1	17160	Risk Ratio (IV, Random, 95% CI)	0.50 [0.42, 0.59]
2.2 Age group 24‐45 years	1	3723	Risk Ratio (IV, Random, 95% CI)	0.78 [0.44, 1.37]
3 CIN3+ associated with HPV16/18, at least 1 dose	2	34562	Risk Ratio (IV, Random, 95% CI)	0.55 [0.45, 0.67]
4 CIN3+ associated with HPV6/11/16/18, at least 1 dose	1	17160	Risk Ratio (IV, Random, 95% CI)	0.54 [0.43, 0.68]
5 AIS associated with HPV16/18, at least 1 dose	2	34562	Risk Ratio (IV, Random, 95% CI)	0.36 [0.17, 0.78]
6 AIS associated with HPV6/11/16/18, at least 1 dose	2	20830	Risk Ratio (IV, Random, 95% CI)	0.40 [0.16, 0.98]
7 Any CIN2+ irrespective of HPV types, at least 1 dose	6	45066	Risk Ratio (IV, Random, 95% CI)	0.79 [0.65, 0.97]
7.1 Age group 15‐26 years	4	35779	Risk Ratio (IV, Random, 95% CI)	0.70 [0.58, 0.85]
7.2 Age group 24‐45 years	2	9287	Risk Ratio (IV, Random, 95% CI)	1.04 [0.83, 1.30]
8 Any CIN3+ HPV type, at least 1 dose	3	35489	Risk Ratio (IV, Random, 95% CI)	0.67 [0.49, 0.93]
8.1 Bivalent vaccine	2	18329	Risk Ratio (IV, Random, 95% CI)	0.55 [0.43, 0.71]
8.2 Quadrivalent vaccine	1	17160	Risk Ratio (IV, Random, 95% CI)	0.81 [0.69, 0.96]
9 Any AIS irrespective of HPV types, at least 1 dose	2	34562	Risk Ratio (IV, Random, 95% CI)	0.32 [0.15, 0.67]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incident HPV16/18 infection, 3 doses	1	368	Risk Ratio (IV, Random, 95% CI)	0.06 [0.02, 0.20]
2 Persistent HPV16/18 infection (6M), 3 doses	1	368	Risk Ratio (IV, Random, 95% CI)	0.02 [0.00, 0.35]
3 Persistent HPV16/18 infection (6M), at least 1 dose	1	10826	Risk Ratio (IV, Random, 95% CI)	0.07 [0.05, 0.09]
4 Persistent HPV16/18 infection(12M), 3 doses	1	368	Risk Ratio (IV, Random, 95% CI)	0.04 [0.00, 0.73]
5 Persistent HPV16/18 infection (12M), at least 1 dose	2	14153	Risk Ratio (IV, Random, 95% CI)	0.08 [0.05, 0.12]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incident HPV16/18 infection, 3 doses	4	8034	Risk Ratio (IV, Random, 95% CI)	0.17 [0.10, 0.31]
2 Incident HPV16/18 infection, at least 1 dose	5	23872	Risk Ratio (IV, Random, 95% CI)	0.23 [0.14, 0.37]
3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis)	3	331	Risk Ratio (IV, Random, 95% CI)	0.47 [0.26, 0.84]
4 Persistent HPV16/18 infection (6M), 3 doses	8	34113	Risk Ratio (IV, Random, 95% CI)	0.07 [0.06, 0.09]
4.1 Age group 15‐26 years	6	27385	Risk Ratio (IV, Random, 95% CI)	0.06 [0.05, 0.08]
4.2 Age group 24‐45 years	2	6728	Risk Ratio (IV, Random, 95% CI)	0.11 [0.06, 0.20]
5 Persistent HPV16/18 infection (6M), at least 1 dose	6	30323	Risk Ratio (IV, Random, 95% CI)	0.12 [0.08, 0.17]
5.1 Age group 15‐26 years	4	22803	Risk Ratio (IV, Random, 95% CI)	0.10 [0.08, 0.12]
5.2 Age group 24‐45 years	2	7520	Risk Ratio (IV, Random, 95% CI)	0.17 [0.10, 0.29]
6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis)	4	1229	Risk Ratio (IV, Random, 95% CI)	0.26 [0.16, 0.44]
6.1 Age group 15‐26 years	2	437	Risk Ratio (IV, Random, 95% CI)	0.12 [0.03, 0.42]
6.2 Age group 24‐45 years	2	792	Risk Ratio (IV, Random, 95% CI)	0.31 [0.18, 0.54]
7 Persistent HPV6/11/16/18 infection (6M), 3 doses	2	4008	Risk Ratio (IV, Random, 95% CI)	0.12 [0.06, 0.21]
8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose	2	4129	Risk Ratio (IV, Random, 95% CI)	0.13 [0.05, 0.37]
9 Persistent HPV16/18 infection (12M), 3 doses	4	22267	Risk Ratio (IV, Random, 95% CI)	0.09 [0.06, 0.13]
10 Persistent HPV16/18 infection (12M), at least 1 dose	5	29464	Risk Ratio (IV, Random, 95% CI)	0.16 [0.12, 0.20]
11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis)	3	3912	Risk Ratio (IV, Random, 95% CI)	0.13 [0.06, 0.33]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incident HPV16/18 infection, at least 1 dose	1	4210	Risk Ratio (IV, Random, 95% CI)	0.24 [0.17, 0.33]
2 Persistent HPV16/18 infection (6M), at least 1 dose	4	33847	Risk Ratio (IV, Random, 95% CI)	0.48 [0.41, 0.57]
2.1 Age group 15‐26 years	2	25199	Risk Ratio (IV, Random, 95% CI)	0.44 [0.38, 0.51]
2.2 Age group 24‐45 years	2	8648	Risk Ratio (IV, Random, 95% CI)	0.57 [0.47, 0.69]
3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose	1	3713	Risk Ratio (IV, Random, 95% CI)	0.52 [0.42, 0.65]
4 Persistent HPV16/18 infection (12M), at least 1 dose	2	24785	Risk Ratio (IV, Random, 95% CI)	0.46 [0.40, 0.54]
5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis)	1	7153	Risk Ratio (IV, Random, 95% CI)	0.18 [0.12, 0.27]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall local/injection site adverse events	8	18113	Risk Ratio (IV, Fixed, 95% CI)	1.18 [1.16, 1.20]
1.1 Bivalent vaccine	2	6503	Risk Ratio (IV, Fixed, 95% CI)	1.29 [1.26, 1.33]
1.2 Quadrivalent vaccine	6	11610	Risk Ratio (IV, Fixed, 95% CI)	1.14 [1.12, 1.16]
2 Pain at injection site	13	25691	Risk Ratio (IV, Random, 95% CI)	1.35 [1.23, 1.49]
2.1 Monovalent vaccine	1	2280	Risk Ratio (IV, Random, 95% CI)	1.05 [1.01, 1.09]
2.2 Bivalent vaccine	8	16897	Risk Ratio (IV, Random, 95% CI)	1.49 [1.26, 1.75]
2.3 Quadrivalent vaccine	4	6514	Risk Ratio (IV, Random, 95% CI)	1.13 [1.07, 1.19]
3 Swelling at injection site	9	22106	Risk Ratio (IV, Random, 95% CI)	1.73 [1.32, 2.27]
3.1 Bivalent vaccine	7	16603	Risk Ratio (IV, Random, 95% CI)	1.62 [1.15, 2.29]
3.2 Quadrivalent vaccine	2	5503	Risk Ratio (IV, Random, 95% CI)	2.79 [0.85, 9.15]
4 Redness at injection site	6	19996	Risk Ratio (IV, Random, 95% CI)	1.72 [1.50, 1.97]
4.1 Quadrivalent vaccine	1	5345	Risk Ratio (IV, Random, 95% CI)	1.46 [1.32, 1.63]
4.2 Bivalent vaccine	5	14651	Risk Ratio (IV, Random, 95% CI)	1.80 [1.53, 2.11]
5 Overall systemic event and general symptoms	8	18191	Risk Ratio (IV, Random, 95% CI)	1.02 [0.98, 1.07]
5.1 Bivalent vaccine	2	6503	Risk Ratio (IV, Random, 95% CI)	1.07 [0.97, 1.19]
5.2 Quadrivalent vaccine	6	11688	Risk Ratio (IV, Random, 95% CI)	1.01 [0.98, 1.04]
6 Serious adverse events	23	71597	Risk Ratio (IV, Random, 95% CI)	0.98 [0.92, 1.05]
6.1 Monovalent vaccine	1	2387	Risk Ratio (IV, Random, 95% CI)	0.95 [0.51, 1.78]
6.2 Bivalent vaccine	15	46231	Risk Ratio (IV, Random, 95% CI)	1.01 [0.96, 1.07]
6.3 Quadrivalent vaccine	7	22979	Risk Ratio (IV, Random, 95% CI)	0.81 [0.65, 1.02]
7 Deaths	23	71176	Risk Ratio (IV, Random, 95% CI)	1.29 [0.85, 1.98]
7.1 Monovalent vaccine	1	2280	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7.2 Bivalent vaccine	15	46231	Risk Ratio (IV, Random, 95% CI)	1.21 [0.66, 2.22]
7.3 Quadrivalent vaccine	7	22665	Risk Ratio (IV, Random, 95% CI)	1.54 [0.73, 3.23]