Long-term effectiveness of the nine-valent human papillomavirus vaccine: Interim results after 12 years of follow-up in Scandinavian women

ABSTRACT

A pivotal study in women aged 16–26 years demonstrated that the nine-valent human papillomavirus (9vHPV) vaccine was efficacious against high-grade cervical dysplasia related to the HPV types covered by the vaccine. To evaluate whether effectiveness remains above 90% for up to 14 years post-vaccination, a long-term follow-up (LTFU) extension of the study was conducted in Denmark, Norway, and Sweden (N = 2,029). Interim findings at 12 years post-vaccination are reported. Effectiveness of the vaccine was measured by comparing the percentage reduction in incidence of HPV16/18/31/33/45/52/58-related high-grade cervical dysplasia in the LTFU cohort with the expected incidence in an unvaccinated cohort. Cervical pre-cancer/cancer diagnoses were identified using national health registries. Tissue samples were obtained from national and regional biobanks for polymerase chain reaction HPV testing, and pathology diagnosis adjudication. Potential waning of vaccine effectiveness and statistical significance were assessed using a control chart method. During LTFU, there were no cases of HPV16/18/31/33/45/52/58-related high-grade cervical dysplasia over 10,396.2 person-years’ follow-up in the per-protocol effectiveness population (n = 1,628). No signals indicated vaccine effectiveness decreasing below 90%. Statistically significant protection was provided by the 9vHPV vaccine through at least 10 years, with complete, although not statistically significant, effectiveness through 12 years.

Main text

The nine-valent HPV (9vHPV) vaccine targets nine HPV types, including HPV16/18/31/33/45/52/58 which cause ~90% of the cervical cancers and a high proportion of HPV-related anal, vaginal, and vulvar cancers, and HPV6/11 which cause ~90% of the genital warts and recurrent respiratory papillomatosis.^1–3 In a randomized, double-blind, quadrivalent human papillomavirus (qHPV) vaccine-controlled efficacy study in young women (Protocol V503–001; NCT00543543; base study), the 9vHPV vaccine demonstrated efficacy against disease related to vaccine-targeted HPV types.^4–6 The design and results of the base study were previously described in detail.^4,5,7,8 In summary, 14,215 women aged 16–26 years from 18 countries were equally randomized to receive a three-dose series of the 9vHPV or qHPV vaccine at Day 1, Month 2, and Month 6. Efficacy, immunogenicity, and safety were assessed at scheduled visits approximately every 6 months through Month 54, with the median follow-up in the base study being 4 years (maximum 6 years) (Figure 1).^4,5,7

Figure 1.

Study design. In the base study, participants received a three-dose series of the 9vHPV or qHPV vaccine at Day 1, Month 2, and Month 6, and were followed for efficacy every 6 months thereafter up to the Month 54 visit. After their last visit in the base study, participants from Scandinavian countries who received 9vHPV vaccine in the base study and provided consent continued for effectiveness follow-up in the study extension (LTFU study). Follow-up in the extension study begins for each participant after their last visit in the base study to ensure continuous follow-up between the base study and the study extension. In the study extension, follow-up for effectiveness is based on a search of national health registries; analyses of data are conducted every two years. The timing of each analysis is shown as a triangle; the timing of the current analysis is shown as an empty triangle. 9vHPV, nine-valent human papillomavirus; LTFU, long-term follow-up; qHPV, quadrivalent human papillomavirus.

Women from Denmark, Norway, and Sweden who participated in the base study were eligible to continue in an LTFU study (Protocol V503–021; NCT02653118), to evaluate whether vaccine effectiveness continues for up to 14 years post-vaccination. The LTFU study design has been described elsewhere (Figure 1).⁹ The LTFU study was initiated on January 1, 2014. Results from a previous interim analysis were encouraging, demonstrating protection conferred by the vaccine through 8 years post-vaccination, i.e., Year 4 of the LTFU study.¹⁰ In this report, we present effectiveness data through up to 12 years post-vaccination i.e., Year 8 of the LTFU study (data cutoff date: January 1, 2022). Follow-up for the LTFU study began the day following the participant’s final visit in the base study.¹⁰ Participants who received at least one dose of 9vHPV vaccine but withdrew from the base study were eligible to enroll in the LTFU study. Follow-up for these participants started after their last visit in the base study.

The study is being conducted in accordance with principles of Good Clinical Practice and received approval from respective ethics committees and/or regulatory agencies, as appropriate. The study was approved by the following ethics committees: the Regional Ethics Review Board in Stockholm, Sweden (Approval No. Dnr: 2013/1016-31); De Videnskabsetiske Komiteer i Region Hovedstaden, Denmark (Case Nos. H-18056634 and H-15015690, Amendment No. 110035); and the Regional Committees for Medical and Health Research Ethics in Norway (REK-reference No. 8489). Informed consent was obtained from participants at the beginning of the base study and for registry-based follow-up in the LTFU study.¹⁰

The primary objective of the LTFU study is to evaluate whether the 9vHPV vaccine remained at least 90% effective for up to 14 years post-vaccination. The primary endpoint was the combined incidence of cervical pre-cancers (cervical intraepithelial neoplasia [CIN]2, CIN3, adenocarcinoma in situ [AIS]), and cervical cancers (referred to as “CIN2 or worse”) related to HPV16/18/31/33/45/52/58. Secondary endpoints include the combined incidence of CIN (any grade), AIS, cervical cancer, vulvar cancer, and vaginal cancer related to HPV6/11/16/18/31/33/45/52/58.

In the Nordic countries, a unique personal identification number is assigned to all residents at birth or immigration. This personal identifier is used all over in the respective countries. This, together with the implementation of national cervical cancer screening programs with centralized administration and registration allowed the LTFU investigators to utilize national health registries to track screening attendance and incidence of cervical pre-cancer/cancer diagnoses. Biennial pre-specified interim analyses allowed for prompt detection of signals indicating waning efficacy of the vaccine during the LTFU study period. The National Registry Study Centers established in participant countries used national screening registries to gather population data, screening results, and follow-up, including pathology diagnoses, endocervical curettage, and definitive therapy.^9,10 Based on these data, relevant slides and tissue samples were obtained from hospital archives and some private laboratories for pathology diagnosis adjudication by the Nordic Pathology Panel (NPP) and for HPV DNA testing via polymerase chain reaction (PCR). The endpoints of clinical cervical, vaginal, and vulvar disease related to a given HPV type were defined by the consensus diagnosis of the NPP along with PCR test results.⁹ Adjacent sections of the tissue block were prepared for pathology diagnosis and PCR testing.^9,11 The pathology diagnosis adjudication process was the same for the base study and LTFU extension.^7,9 The same multiplex PCR assay used in the base study and qHPV vaccine clinical development program was employed to detect the presence of HPV DNA.^4,10,12,13

The primary endpoint was calculated as a percentage reduction in the incidence of HPV-related CIN2 or worse in the LTFU cohort compared with an unvaccinated cohort of similar age and risk exposure to determine vaccine effectiveness. Incidence of HPV-related disease in an unvaccinated population came from Denmark, Norway, and Sweden, collected prior to the introduction of the HPV vaccination. In this Concomitant Cohort Study, information on lifestyle and sexual habits from 70,000 women across four Nordic countries in 2004–2005, was collected prior to introduction of the HPV vaccine.¹⁴ The estimated incidence of CIN2 or worse in the unvaccinated cohort (aged 23–29 years with one to six sexual partners) was 548 per 100,000 person-years.¹⁰ Based on the fact that ~80% of HPV-related CIN2 or worse lesions are associated with HPV16/18/31/33/45/52/58 in Europe,^9,15 the estimated incidence of CIN2 or worse related to these nine valent vaccine types is 438 per 100,000 person-years.⁹ The incidence rate of disease was monitored in real-time during the LTFU study using an adapted Poisson Shewhart control chart method, as previously described.⁹ Vaccine effectiveness falling below 90% was indicated by upper monitoring bounds (upper control limits) to determine whether the incidence of breakthrough disease exceeded 43.8/100,000 person-years. The observed number of endpoint cases were plotted and compared with the upper control limits for 2-year intervals. Analyses were conducted in the per-protocol effectiveness (PPE) population of participants who received all three doses of the 9vHPV vaccine within 1 year, were seronegative at Day 1 and PCR-negative from Day 1 to Month 7 of the base study for the HPV type being analyzed, and had no protocol violations that could affect the evaluation of vaccine efficacy.

In the base study, 2,223 participants from Denmark, Norway, and Sweden received at least one dose of the 9vHPV vaccine.¹⁰ Of those, 2,029 consented to the registry-based LTFU effectiveness analyses. For this interim analysis, participants were followed for effectiveness for up to 13.6 years post-Dose 3 (median: 10.4 years) or 14.1 years post-Dose 1 (median: 10.9 years). Most (n = 1,919/2,029, 94.6%) participants had at least one cervical cytology/HPV screening visit during the LTFU period covered by this analysis (Denmark: n = 1,580/1,653, 95.6%; Norway: n = 301/318, 94.7%; Sweden: n = 38/58, 65.5%).

There were no observed cases of HPV16/18/31/33/45/52/58-related CIN2 or worse during the LTFU period, indicating a vaccine effectiveness of 100% (95% CI, 91.9–100) during this period (Table 1). Based on the 10,396.2 person-years of follow-up time accrued during the LTFU study period and the estimated incidence rate of 438 per 100,000 person-years in an unvaccinated cohort, no more than two cases of HPV16/18/31/33/45/52/58-related CIN2 or worse were expected if vaccine effectiveness was maintained at ≥90%.

Table 1.

Analysis of 9vHPV vaccine effectiveness against HPV16/18/31/33/45/52/58-related CIN2, CIN3, AIS, and cervical cancer by time since 9vHPV vaccination, HPV type, and lesion type (PPE population)^a.

Young women 16–26 years of age (N = 2,029)
	Cases/n	Person-years’ follow-up	Rate per 100,000 person-years (95% CI)	Vaccine effectiveness,b % (95% CI)
From the start of the LTFU study
HPV16/18/31/33/45/52/58-related CIN2 or worsec	0/1,628	10,396.2	0.0 (0.0–35.5)	100 (91.9–100)
By time since start of the LTFU study
>0 to 2 yearsd	0/1,628	3,214.0	0.0 (0.0–114.8)
>2 to 4 yearsd	0/1,583	3,086.2	0.0 (0.0–119.5)
>4 to 6 yearsd	0/1,481	2,717.1	0.0 (0.0–135.8)
>6 to 8 yearsd	0/1,089	1,326.0	0.0 (0.0–278.2)
>8 to 10 yearsd	0/178	53.0	0.0 (0.0–6,965.3)
From the start of the base study
HPV16/18/31/33/45/52/58-related CIN2 or worsee	1/1,691	16,340.8	6.1 (0.2–34.1)
By time since 9vHPV vaccine Dose 1
>0 to 4 yearsf	1/1,691	5,681.6	17.6 (0.4–98.1)
>4 to 6 yearsd	0/1,633	3,222.7	0.0 (0.0–114.5)
>6 to 8 yearsd	0/1,585	3,097.0	0.0 (0.0–119.1)
>8 to 10 yearsd	0/1,494	2,763.1	0.0 (0.0–133.5)
>10 to 12 yearsd	0/1,156	1,464.4	0.0 (0.0–251.9)
>12 to 14 yearsd	0/266	111.8	0.0 (0.0–3,298.1)
By HPV type
HPV16-related	0/1,315	12,927.5	0.0 (0.0–28.5)
HPV18-related	1/1,480	14,384.2	7.0 (0.2–38.7)
HPV31-related	0/1,455	14,188.5	0.0 (0.0–26.0)
HPV33-related	0/1,525	14,832.0	0.0 (0.0–24.9)
HPV45-related	0/1,598	15,463.9	0.0 (0.0–23.9)
HPV52-related	0/1,496	14,524.2	0.0 (0.0–25.4)
HPV58-related	0/1,544	15,031.4	0.0 (0.0–24.5)
By lesion type
CIN2 or CIN3	1/1,691	16,340.8	6.1 (0.2–34.1)
CIN2	1/1,691	16,340.8	6.1 (0.2–34.1)
CIN3	0/1,691	16,341.2	0.0 (0.0–22.6)
AIS	0/1,691	16,341.2	0.0 (0.0–22.6)
Cervical cancer	0/1,691	16,341.2	0.0 (0.0–22.6)

Note: N = number of participants who received at least one dose of 9vHPV vaccine and consented to effectiveness follow-up.

n = number of PPE-eligible participants who have at least one follow-up visit. During the LTFU study, a follow-up visit represents retrieval of cervical cytology or cervical, vulvar, or vaginal tissue sample collection record from the relevant national health registry.

^aThe PPE population included participants who received all three doses of vaccine within 1 year, were seronegative at Day 1 and PCR-negative from Day 1 to Month 7 of the base study for the HPV type being analyzed, and had no protocol violations that could affect the evaluation of vaccine prophylactic efficacy.

^bVaccine effectiveness measures the relative reduction of the disease incidence in vaccine recipients compared with a background incidence rate of 438 per 100,000 person-years, based on the incidence in an unvaccinated cohort.

^cFor an individual participant, total person-years’ follow-up was calculated as the number of years starting from the beginning of the LTFU study (either the date when the participant reached the base study Year 4 or exited from the base study, whichever was later) through the date of the participant’s latest cervical cytology or cervical, vulvar, or vaginal tissue sample collection record obtained from the relevant national health registry.

^dFor an individual participant with cervical cytology or cervical, vulvar, or vaginal tissue sample collection record obtained from the relevant national health registry within the indicated time interval, total person-years’ follow-up was calculated as the number of years starting from the date when the participant reached the beginning of the indicated time interval through either the date when the participant reached the end of the indicated time interval or the date of the participant’s latest cervical cytology or cervical, vulvar, or vaginal tissue sample collection record obtained from the relevant national health registry, whichever is earlier.

^eFor an individual participant, total person-years’ follow-up was calculated as the number of years starting from the date when the participant reached Month 7 of the base study (the case counting start time in the per-protocol efficacy population) through the date of the participant’s latest cervical cytology or cervical, vulvar, or vaginal tissue sample collection record from the relevant national health registry.

^fThis time interval covers the base study period. For an individual participant, total person-years’ follow-up was calculated as the number of years starting from the date when the participant reached Month 7 of the base study through either the date when the participant reached the base study Year 4 or exited the base study, whichever is earlier.

9vHPV, nine-valent human papillomavirus; AIS, adenocarcinoma in situ; CI, confidence interval; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LTFU, long-term follow-up; PCR, polymerase chain reaction; PPE, per-protocol effectiveness.

Statistical methodology for the observed vaccine effectiveness over time and detection of signals of waning vaccine effectiveness are reported in prior publications.^9,16 To draw firm conclusions, at least 2,140 person-years of follow-up (60% of the total expected person-years of follow-up time) in any given 2-year interval since the start of the LTFU study are required.^9,16 From 4 to 6 years since the start of the LTFU study, a total of 2,717 person-years have been accrued, which is sufficient to conclude that the 9vHPV vaccine remained effective through at least 10 years post-vaccination (Table 1). During the evaluable time period, no points crossed the pre-specified 1.83- or 2.75-sigma control limits (Figure 2), indicating no signal of waning vaccine effectiveness in the PPE population through at least 10 years post-vaccination. This pattern continued in the interval up to 12 years. However, the follow-up time accrued in the 10- to 12-year interval is as yet insufficient to definitively conclude that the vaccine is effective beyond 10 years.

Figure 2.

Control chart analysis of the effectiveness of the 9vHPV vaccine against HPV16/18/31/33/45/52/58-related CIN2, CIN3, AIS, and cervical cancer in the PPE population. The incidence of HPV-related disease was evaluated at 2-year intervals during the LTFU period and, if plotted incidences crossed the 1.83- and 2.75-sigma control limits of the control chart, an inference was made that the accumulating data were indicative of waning effectiveness. Shaded intervals indicate intervals with insufficient follow-up time to declare statistical significance. The center line indicates the expected count in each interval. 9vHPV, nine-valent human papillomavirus; AIS, adenocarcinoma in situ; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LTFU, long-term follow-up; PPE, per-protocol effectiveness.

Since the start of the LTFU study, no new reported cases of the secondary endpoint of HPV6/11/16/18/31/33/45/52/58-related CIN (any grade), AIS, cervical cancer, vulvar cancer, or vaginal cancer have been observed (Table 2).

Table 2.

Incidence of HPV6/11/16/18/31/33/45/52/58-related CIN (any grade), AIS, cervical cancer, vulvar cancer, and vaginal cancer by time since 9vHPV vaccination, HPV type, and lesion type (PPE population)^a.

	Young women 16–26 years of age (N = 2,029)
From the start of the base study	Cases/n	Person-years’ follow-up	Rate per 100,000 person-years (95% CI)
HPV6/11/16/18/31/33/45/52/58-related CIN (any grade), AIS, cervical cancer, vulvar cancer, or vaginal cancerb	2/1,706	17,108.9	11.7 (1.4–42.2)
By time since 9vHPV vaccine Dose 1
>0 to 4 yearsc	2/1,706	5,824.4	34.3 (4.2–124.0)
>4 to 6 yearsd	0/1,704	3,383.4	0.0 (0.0–109.0)
>6 to 8 yearsd	0/1,667	3,265.0	0.0 (0.0–113.0)
>8 to 10 yearsd	0/1,581	2,932.4	0.0 (0.0–125.8)
>10 to 12 yearsd	0/1,234	1,582.3	0.0 (0.0–233.1)
>12 to 14 yearsd	0/292	121.3	0.0 (0.0–3,040.3)
By HPV type
HPV6-related	0/1,340	13,431.8	0.0 (0.0–27.5)
HPV11-related	0/1,340	13,431.8	0.0 (0.0–27.5)
HPV16-related	0/1,319	13,213.7	0.0 (0.0–27.9)
HPV18-related	1/1,488	14,906.6	6.7 (0.2–37.4)
HPV31-related	1/1,464	14,698.1	6.8 (0.2–37.9)
HPV33-related	0/1,537	15,422.3	0.0 (0.0–23.9)
HPV45-related	0/1,612	16,168.8	0.0 (0.0–22.8)
HPV52-related	0/1,506	15,103.6	0.0 (0.0–24.4)
HPV58-related	0/1,558	15,631.0	0.0 (0.0–23.6)
By lesion type
CIN1	1/1,692	16,341.6	6.1 (0.2–34.1)
CIN2 or CIN3	1/1,691	16,340.8	6.1 (0.2–34.1)
CIN2	1/1,691	16,340.8	6.1 (0.2–34.1)
CIN3	0/1,691	16,341.2	0.0 (0.0–22.6)
AIS	0/1,691	16,341.2	0.0 (0.0–22.6)
Cervical cancer	0/1,691	16,341.2	0.0 (0.0–22.6)
Vulvar cancer	0/1,705	17,116.8	0.0 (0.0–21.6)
Vaginal cancer	0/1,705	17,116.8	0.0 (0.0–21.6)

Note: N = number of participants who received at least one dose of 9vHPV vaccine and consented to effectiveness follow-up.

n = number of PPE-eligible participants who have at least one follow-up visit. During the LTFU study, a follow-up visit represents retrieval of cervical cytology or cervical, vulvar, or vaginal tissue sample collection record from the relevant national health registry.

^aThe PPE population included participants who received all three doses of vaccine within 1 year, were seronegative at Day 1 and PCR-negative from Day 1 to Month 7 of the base study for the HPV type being analyzed and had no protocol violations that could affect the evaluation of vaccine prophylactic efficacy.

^bFor an individual participant, total person-years’ follow-up was calculated as the number of years starting from the date when the participant reached Month 7 of the base study (the case counting start time in the per-protocol efficacy population) through the date of the participant’s latest cervical cytology or cervical, vulvar, or vaginal tissue sample collection record from the relevant national health registry.

^cThis time interval covers the base study period. For an individual participant, total person-years’ follow-up was calculated as the number of years starting from the date when the participant reached Month 7 of the base study through either the date when the participant reached the base study Year 4 or exited the base study, whichever is earlier.

^dFor an individual participant with cervical cytology or cervical, vulvar, or vaginal tissue sample collection record obtained from the relevant national health registry within the indicated time interval, total person-years’ follow-up was calculated as the number of years starting from the date when the participant reached the beginning of the indicated time interval through either the date when the participant reached the end of the indicated time interval or the date of the participant’s latest cervical cytology or cervical, vulvar, or vaginal tissue sample collection record obtained from the relevant national health registry, whichever is earlier.

9vHPV, nine-valent human papillomavirus; AIS, adenocarcinoma in situ; CI, confidence interval; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LTFU, long-term follow-up; PCR, polymerase chain reaction; PPE, per-protocol effectiveness.

One case of HPV18-related CIN2 and one case of HPV31-related CIN1 were observed during the base study (Tables 1 and 2).¹⁰ The participant with HPV18-related CIN2 was diagnosed at Month 24 with a cervical biopsy positive for HPV58 and endocervical curettage positive for HPV18 and HPV58. This participant was positive for HPV58 at baseline and at all study visits until diagnosis. She was positive for HPV18 only at the Month 12 visit and at time of diagnosis. Therefore, HPV18 most likely did not cause the lesion. The participant with CIN1 was diagnosed at Month 7, with cervical definitive therapy performed following a diagnosis of HPV51-positive CIN2 and testing positive for HPV31 and 51. The participant was positive for HPV51 at all visits from Months 7 to 24, and only positive for HPV31 with the cervical definitive therapy sample at Month 7. Therefore, HPV31 most likely did not cause the lesion.¹⁰

Because participants in this study represent a cohort who received the 9vHPV vaccine at least five years before it became commercially available, any evidence of waning vaccine effectiveness observed in this study would allow for the implementation of public health decisions (e.g., requiring a booster dose) prior to the general population being affected by reduced protection.⁹ The results of the control chart method have demonstrated statistically significant vaccine effectiveness of at least 90% through at least 10 years post-vaccination, with indications of continuing effectiveness through up to 12 years. These results are based on conservative estimates of HPV incidence using survey data from 2004–2005. Recent data suggest an increase in HPV exposure, reinforcing the observed high efficacy of the vaccine.¹⁷

HPV vaccination programs were introduced in preadolescent girls in Scandinavia around 2009.¹⁸ However, any herd protection resulting from these vaccination programs is unlikely to have a substantial effect on the LFTU study results since vaccination in the base study was initiated between 2007 and 2009 before vaccination programs were widely implemented. Also, the base study participants were 16 to 26 years of age at enrollment, an age group different from the target population of vaccination programs. As previously reported in a systematic literature review and meta-analysis, significant reductions in high-grade cervical lesions were found in girls aged 15–19 years (vaccination program target cohort), but not in women aged 20 years and older, demonstrating an age-group effect of vaccination programs.¹⁹ Nonetheless, we cannot entirely exclude that herd protection may have had some impact.

Real-world studies have demonstrated the effectiveness of HPV vaccines, demonstrated by the decreased prevalence of HPV types covered by the vaccine as well as reduced rates of high-grade cervical lesions^20–23 and cervical cancer^24–28 among vaccinated individuals. In addition, 9vHPV vaccine safety data from large post-marketing surveillance and epidemiologic studies have been consistent with findings of clinical trials.^29–32 The results of this 12-year interim analysis expand on findings from the previous 8-year interim analysis,¹⁰ and together with other LFTU results³³ provide further evidence for a favorable long-term benefit for the 9vHPV vaccine.

Funding Statement

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Medical writing assistance, under the direction of the authors, was provided by Nithu Mariya Johnson, PharmD, of CMC AFFINITY, a division of IPG Health Medical Communications, in accordance with Good Publication Practice (GPP 2022) guidelines. This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure statement

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Merck is the manufacturer of the 9vHPV vaccine.

Susanne K. Kjaer reports grants through her affiliating institute from MSD during the conduct of the study.

Thea E. Hetland Falkenthal reports research grants to her institution from MSD during the conduct of the study and research grants to her institution for other register-based studies on HPV vaccination in Norway.

Karin Sundström reports research grants from MSD to her institution for the present work on HPV vaccination in Sweden and research grants and consulting fees to her institution for other register-based studies on HPV vaccination in Sweden.

Christian Munk reports that his host institution received research grants from MSD during the conduct of the study.

Tina Sture reports research grants to her institution from MSD during the conduct of the study and research grants to her institution for other register-based studies on HPV vaccination in Norway.

Oliver Bautista, Thomas Group, Sonali Rawat, and Alain Luxembourg are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock or stock options in Merck & Co., Inc., Rahway, NJ, USA.

Abbreviations

9vHPV, nine-valent human papillomavirus; AIS, adenocarcinoma in situ; CI, confidence interval; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LTFU, long-term follow-up; NPP, Nordic Pathology Panel; NRSC, National Registry Study Centers; PCR, polymerase chain reaction; PPE, per-protocol effectiveness; qHPV, quadrivalent human papillomavirus.

Author contributions statement

Oliver Bautista, Thomas Group, Sonali Rawat, and Alain Luxembourg contributed to the analysis and interpretation of data.

Susanne K. Kjaer, Thea E. Hetland Falkenthal, Karin Sundström, Christian Munk, and Tina Sture contributed to the acquisition and interpretation of data.

Each author critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Biographical statement

Susanne Krüger Kjaer is a medical doctor and professor in cancer epidemiology with a focus on gynecological cancer. She is heading a research department working on early detection and prevention of cancer by identification of lifestyle, socioeconomic, and genetic risk factors, and other biomarkers to prevent cancer development and improve morbidity and survival from cancer.

The main part of the research falls within molecular biological epidemiology with most of the studies being multidisciplinary. She has established large population-based cohorts with collection of information on lifestyle factors as well as biological samples. Prof. Kjaer’s research has contributed substantial knowledge on the natural history of HPV and cervical neoplasia.