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Monitoring the HPV vaccination program in The Netherlands

Donken, R.

2018

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citation for published version (APA)

Donken, R. (2018). Monitoring the HPV vaccination program in The Netherlands: Effects, changing schedule

and future perspective.

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CHAPTER 2

High eﬀ ectiveness of the bivalent

HPV vaccine up to six years

post-vaccination against incident

and persistent HPV infections in

young Dutch females

Robine Donken Audrey J. King Johannes A. Bogaards Petra J. Woestenberg Chris J.L.M. Meijer Hester E. de Melker

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2 ABSTRACT

Background

Monitoring vaccine effectiveness (VE) in vaccination programs is of importance for assessing the impact of immunization. This study aims to estimate the VE of the bivalent HPV-vaccine against incident and 12-month persistent infections up to six years post-vaccination.

Methods

In 2009/2010, girls eligible for the vaccination catch-up campaign (14-16 years of age) were enrolled into a prospective cohort. Annually, participants filled out a questionnaire and handed in a vaginal self-swab for HPV testing by SPF10-

LiPA₂₅.We compared socio-demographics and infection rates between vaccinated and unvaccinated girls. The VE was adjusted for characteristics related to HPV vaccination status. We used combined endpoints for VE estimation.

Results

In total 1635 women, of whom 54% were fully vaccinated, were included for VE estimation. The adjusted VE against HPV16/18 persistent infections amounted to 97.7% (83.5-99.7%). We found a VE against HPV31/33/45 persistent infections of 61.8% (16.7-82.5%). We found no indications that the protection against vaccine or cross-protective types changes over time.

Conclusion

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INTRODUCTION

The human papillomavirus (HPV) is the most common sexually transmitted infection.[1] HPV infection is estimated to cause 5% of all cancers worldwide, both in men and women.[2] The most common cancer associated with HPV among women is cervical cancer, which is the fourth most common cause of cancer among women globally.[3] Since 2006, three prophylactic HPV vaccines have been registered. As many other countries, the Netherlands has implemented HPV vaccination in their National Immunization Program (NIP).[4] HPV vaccination started in 2009 with a catch-up campaign (uptake 52.3%) for birth cohorts 1993 till 1996. From 2010 onwards, girls are vaccinated in the year they turn thirteen (birth cohort 1997 and further).[5] To date, all birth cohorts are vaccinated with the bivalent HPV vaccine, which protects against HPV16/18 associated with approximately 70% of all cervical cancers. However, the proportions of HPV16/18 positive cervical cancers vary by geographical region, with somewhat higher relative contributions in Europe (73%) and North America (79%).[6]

Alongside the introduction of the HPV vaccine into the Dutch NIP, the Health Council advised to closely monitor the HPV vaccination program.[7] As cervical cancer screening in the Netherlands only starts at the age of 30 years [8, 9], it will take a long time before the effects of HPV vaccination on clinical endpoints will become apparent through this program. Meanwhile the use of intermediate endpoints, such as persistent HPV infections, will give indications on the effects of the HPV vaccination program.[9] This study aimed to estimate the vaccine effectiveness (VE) of the bivalent HPV-vaccine against incident and persistent infections up to six years post-vaccination, by comparing vaccinated and unvaccinated young women in a prospective cohort study drawn from the general Dutch population.

METHODS

Study design

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participate in a prospective cohort study on HPV Amongst Vaccinated And Non-vaccinated Adolescents (HAVANA). Of these invited girls, 1832 girls (6.3%) consented to participate. The baseline measurement was performed (approximately 1 month) before vaccination was offered. Both vaccinated and unvaccinated girls were included in the study. Vaccination status of participants was acquired through the national vaccination registration system Praeventis®.[12] Yearly among all participants a web-based questionnaire and vaginal self-swab (Viba-Brush®, Rovers Medical Devices, Oss, the Netherlands) are collected. This study adhered to the tenets of the Declaration of Helsinki [13] and was approved by the Medical Ethics Committee of the VU University Medical Center in Amsterdam (2009/022). This paper describes data up to six years post-vaccination.

Detection of HPV DNA

Brush samples were stored in 1 ml of phosphate buffered saline for DNA analysis. Until analyses, swabs were stored at -20°C. DNA extraction was performed using MagNA Pure LC (Total Nucleic Acid Isolation Kit, Roche, Mannheim, Germany) and eluted in 100 μl elution buffer. The sensitive SPF₁₀ primer set was used to amplify HPV DNA. A DNA enzyme-linked immunoassay (HPV-DEIA, DDL Diagnostics Laboratory, Rijswijk, the Netherlands) was used to detect the amplified HPV DNA. Amplicons of samples positive in the HPV-DEIA were genotyped with the reverse line blot assay (HPV-LiPA, DDL Diagnostics Laboratory, Rijswijk, the Netherlands) which is able to detect 25 HPV genotypes. This assay is able to distinguish the following high-risk (hr) types: HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. Additionally, the assay can detect the following low risk (lr) types: HPV6, 11, 34, 40, 42, 43, 44, 53, 54, 66, 70 and 74. Also HPV 68, 73 and 97 can be detected, however these types cannot be distinguished and are therefore all classified as HPV68. HPV68 is considered as putative high-risk.[10]

Statistical analyses

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Differences in socio-demographic and sexual risk factors over time between vaccinated and unvaccinated women where explored using Generalized Estimating Equation (GEE) models with an exchangeable correlation structure. Dichotomous outcomes were analyzed by a binomial model with logit link, resulting in odds ratios (OR) as the measure of association. For continuous outcomes we assumed a normal distribution and estimated a mean difference between vaccinated and unvaccinated participants. For outcomes being count data we used a Poisson distribution, which estimated the rate difference between vaccinated and unvaccinated participants. Potential risk factors were used as dependent variables and vaccination status as independent variable. First, we checked whether the development over time was different between vaccinated and unvaccinated participants, by checking the interaction between time and vaccination status. Therefore we added time (as continuous factor) and the interaction between vaccination status and time as independent variables to the model. If a significant interaction was observed, we reported the estimates of the model including the interaction. This would result in three estimates, one for the vaccination status at baseline, one for time (round of study) and one for the interaction between time and vaccination status. If no significant interaction was observed the overall estimate (across all time-points) for vaccination status was reported.

For all rounds type-specific HPV prevalence was determined among all participants who had provided a swab for that specific round, independent of their baseline status. Incidence was defined as being HPV positive for a specific HPV type at that round, preceded by a negative sample in the previous round. Persistence was defined as being HPV positive for a specific HPV type in two consecutive rounds, preceded by a negative sample. We calculated the type-specific incidence and persistence rates, by GEE with a Poisson distribution, during follow-up in both vaccinated and unvaccinated participants for hr and lr types.

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cross-2

protective types, we combined the HPV types 31/33/45, for which types consistent cross-protective efficacy against 6-month persistent infection and CIN2+ was observed in the PATRICIA trial.[14, 15] The VE was estimated using the Prentice Williams Peterson total time approach (PWP-TT). This is an extension of Cox regression which is able to take into account recurrent events. This method takes into account an event-specific hazard for subsequent events.[16] Event-specific hazards were adjusted for time-dependent covariates by taking observed values at the each subsequent event. VE was calculated as 1 minus the hazard ratio times 100%. The model for the adjusted VE included characteristics that were significantly (p<0.05) related with HPV vaccination status in the GEE analysis. In order to examine the influence of time since vaccination on the VE estimate, we stratified the VE estimates by years since vaccination. Also, the proportionality of hazards over time between vaccinated and unvaccinated participants was explored by adding an interaction term between time and vaccination status to the model. All analyses were performed using SAS 9.4 (SAS Institute INC., Cary, NC, USA).

Sensitivity analyses

In sensitivity analyses, we calculated incidence and persistence rates when instead of one, two rounds between recurrent infections should be negative. Because of the risk for cervical lesions of long-term hrHPV infections, in consultation with the medical ethics committee, girls who were positive for the same hrHPV type in three consecutive rounds with a clinically validated test, should be referred to a gynecologist for further examination. Therefore girls tested positive with the SPF10 assay in three consecutive rounds were retested with the clinically validated

GP5+/6+ algorithm [17]. If this resulted also in three positive tests for the same hrHPV types girls were referred to a gynecologist. In sensitivity analyses we censored participants for all HPV types from the moment they were referred to the gynecologist.

RESULTS

Participant characteristics

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Table 1. To describe the characteristics over time we first checked whether there was a difference in development over time between vaccinated and unvaccinated, by exploring possible interaction between time and vaccination status. If no significant interaction was observed, we reported an overall (for all rounds) estimate. Vaccinated participants were slightly younger than unvaccinated participants (mean difference -0.14, 95% CI -0.21--0.07). At baseline, vaccinated participants were less likely to live in areas with a lower urbanization degree (OR 0.33 95% CI 0.26-0.43). This difference diminished over time (OR 1.05 95% CI 1.01-1.11 for the interaction between time and vaccination status), but at round six vaccinated participants were still less likely to live in areas with a lower urbanization degree (OR 0.46 95% CI 0.35-0.60). At baseline no difference between vaccinated and unvaccinated participants (OR 0.93 95% CI 0.74-1.15) was observed with regard to contraceptive use (any type). However, over time vaccinated participants became more likely to use contraceptives. At round six vaccinated participants had an OR of 3.14 (95%CI 1.77-5.59) of ever used contraceptives compared with unvaccinated. At baseline, no significant differences were observed between vaccinated and unvaccinated participants with regard to smoking (OR 0.83 95%CI 0.67-1.01) or sexual experience (OR 0.86 95%CI 0.70-1.05). Over time, vaccinated participants become more likely to ever had smoked or had sex, as evidenced by significant interactions between time and vaccination status. At round six, differences between vaccinated and unvaccinated in ever smoked (OR 1.08 95%CI 0.84-1.38) or ever had sex (OR 1.42 95%CI 0.94-2.15) were not significant.(Table 1A) Among sexually experienced participants, additional questions regarding sexual behavior were posed. We did not observe a difference between vaccinated and unvaccinated sexually experienced participants in any of these questions. (Table 1B)

Prevalence, incidence and persistence of HPV DNA

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most prevalent low-risk types (Figure 1B). The incidence rate for HPV16 among unvaccinated participants was 22.7 (95% CI 18.0-28.6) per 1000 person-years (py) compared with 3.7 (95%CI 2.2-6.4) per 1000 py. For HPV 18, this was respectively 11.7 (95%CI 8.5-16.2) and 4.0 (95%CI 2.4-6.8) per 1000 py. For persistent infections among vaccinated the rate was low, 0.3 (95%CI 0.0-2.1) per 1000 py for HPV16, for HPV 18 no infections were observed (persistence rate 0.0 95%CI 0.0-1.1). Among unvaccinated the persistence rates were respectively 9.5 (95%CI 6.6-13.7) per 1000 py for HPV 16 and 4.0 (95%CI 2.2-6.9) per 1000 py for HPV18. (Supplementary A)

Vaccine effectiveness

VE estimates were adjusted for factors associated with vaccination status: age, urbanization degree, ever smoked, ever used contraception, ever had sex. We calculated the unadjusted and adjusted VE against type-specific incident and persistent infections with high-risk HPV types. (Figure 2) We did observe a significant unadjusted and adjusted VE for HPV16, 18, 31 and 45 incident infections, in addition the adjusted VE against incident infections of HPV35 was also significant. For persistent infections a significant (un)adjusted VE was observed for HPV16, 18 and 31.

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Figure 1A. Type-specific HPV prevalence for high-risk types during follow-up among vaccinated and

unvaccinated participants of the HAVANA-study.

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Figure 1B. Type-specific HPV prevalence for low-risk types during follow-up among vaccinated and

unvaccinated participants of the HAVANA-study.

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Figure 2. (Un)adjusted type-specific vaccine effectiveness against incident and persistent infections up to six

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Figure 3. (Un)adjusted vaccine effectiveness against incident and persistent infections up to six years

post-vaccination.

Nonavalent includes all nine-types included in the nonavalent HPV vaccine (HPV6/11/16/18/31/33/45/52/58), while nonavalent hrHPV, includes only the seven hrHPV types (HPV16/18/31/33/45/52/58) included in the nonavalent vaccine. α9 hrHPV types includeHPV16/31/33/35/52/58, α7 hrHV types include HPV18/39/45/59.

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Sensitivity analyses

We found the same HPV types to have significantly lower incidence or persistence rates in vaccinated participants when at least two negative measurements between consecutive infections were required for incidence and persistence (Supplementary C). Censoring participants (n=13) when they were referred to a gynecologist did not influence our VE estimates (data not shown).

DISCUSSION

We estimated the VE against incident and 12-month persistent HPV infections up to six years post-vaccination in an ongoing longitudinal observational study among vaccinated and unvaccinated women in the Netherlands. We found a very high VE against incident and persistent infections by vaccine types HPV16/18 and good cross-protection against HPV31/33/45 combined. We did not find indications that protection for vaccine or cross-protective types wanes over time. These findings are reassuring with regard to expected benefits of the bivalent HPV vaccination program on a population-level.

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VE (but not significantly different) has been shown in girls vaccinated at the age of 12-13 years (VE 85.1% 95%CI 77.3-90.9%).[20] Recently Tota et al. suggested some protective effect against incident infections with HPV35, 52 and 58 by combining data from the Costa Rica Vaccine Trial and PATRICIA Trial.[21] After adjustment, we also observed cross-protection against HPV35 incident infections (adjusted VE 70.8% 95%CI 8.1-90.7%), but we did not find an indication for a cross-protective effect against HPV52 and HPV58.

We did not observe a difference in protection over time, neither for vaccine types nor for cross-protective types. Hence, no indications were found for waning of protection in our study population up to six years post-vaccination. This is in line with recent findings of a Dutch study among STI clinic visitors[22] and a Scottish study [20], where no indications for waning of protection of vaccine types and cross-protective types was observed against prevalent HPV infections. These finding are in contrast to a meta-analysis of vaccination trials.[23] It could be that women in the studies included in this meta-analysis were more frequently exposed to HPV than our study participants, e.g. trial participants were older than our study participants. On the other hand, differences between studies included in the meta-analysis might be explained by systematic differences between study populations or trial protocols. Our longitudinal follow-up study is appropriate to detect a change in protection over time, but might be underpowered due to the limited exposure of our cohort at this time. Further follow-up of our cohort study is needed to confirm that there is indeed no waning of protection, or that the effect might become visible later over time in our cohort.

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HPV vaccination [24, 26]. Besides comparability with regard to socio-demographic and sexual risk factors, comparability with regard to exposure to HPV can be examined. We did not observe a significant difference between vaccinated and unvaccinated participants for prevalence of any HPV.

In contrast to post-hoc analyses of the PATRICIA trial, where significant protection against HPV6/11 six-month persistent infections was observed[27], we did not observe an effect of the bivalent vaccine against HPV6/11 incident and persistent infections in our study. These findings are in line with a previous Dutch study, where no effect of the bivalent vaccine was found against HPV6/11 prevalence among STI clinic visitors. However, that study did find a non-significant partially protective effect on anogenital warts.[28] Data from England have shown a significant decline in genital warts after the introduction of the bivalent vaccine for young girls and heterosexual men.[29]

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REFERENCES

1. Syrjanen K, Hakama M, Saarikoski S, et al. Prevalence, incidence, and estimated life-time risk of cervical human papillomavirus infections in a nonselected Finnish female population. Sex Transm Dis 1990; 17:15-9. 2. de Martel C, Plummer M, Vignat J, Franceschi

S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 2017.

3. World Health Organization. Human papillomavirus (HPV) and cervical cancer, Fact sheet. Available at: http://www.who.int/ mediacentre/factsheets/fs380/en/.

4. Bruni L, Diaz M, Barrionuevo-Rosas L, et al. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. Lancet Glob Health 2016; 4:e453-63.

5. van Lier E, Oomen P, Mulder M, Conyn-van Spaendonck M, Drijhout I, de Hoogh P. Vaccinatiegraad Rijksvaccinatieprogramma Nederland Verslagjaar 2013: RIVM report 2014.

6. de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11:1048-56.

7. Gezondheidsraad. Advies vaccinatie baar-moederhalskanker, 2008.

8. Gezondheidsraad. Advies screening baar-moederhalskanker, 2011.

9. HPV working Group. Primary End-Points for Prophylactic HPV Vaccine Trials. IARC, 2014. 10. Mollers M, King AJ, Knol MJ, et al. Effectiveness of human papillomavirus vaccine against incident and persistent infections among young girls: Results from a longitudinal Dutch cohort study. Vaccine 2015; 33:2678-83. 11. Mollers M, Scherpenisse M, van der Klis FR,

et al. Prevalence of genital HPV infections and HPV serology in adolescent girls, prior to vaccination. Cancer Epidemiol 2012; 36:519-24.

12. van Lier A, Oomen P, de Hoogh P, et al. Praeventis, the immunisation register of the Netherlands: a tool to evaluate the National Immunisation Programme. Euro surveillance : 2012; 17.

13. World Medical Association. Declaration of Helsinki. Available at: http://www.wma.net/ en/30publications/10policies/b3.

14. European Medicines Agency. EPAR Product Information Cervarix.

15. Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009; 374:301-14.

16. Donken R, Knol MJ, Ogivlie GS, et al.. Measuring vaccine effectiveness against persistent HPV infections: a comparison of different statistical approaches. Manuscript in preparation.

17. Hesselink AT, van Ham MA, Heideman DA, et al. Comparison of GP5+/6+-PCR and SPF10-line blot assays for detection of high-risk human papillomavirus in samples from women with normal cytology results who develop grade 3 cervical intraepithelial neoplasia. J Clin Microbiol 2008; 46:3215-21. 18. Lehtinen M, Dillner J. Clinical trials of human

papillomavirus vaccines and beyond. Nat Rev Clin Oncol 2013; 10:400-10.

19. Apter D, Wheeler CM, Paavonen J, et al. Efficacy of human papillomavirus 16 and 18 (HPV-16/18) AS04-adjuvanted vaccine against cervical infection and precancer in young women: final event-driven analysis of the randomized, double-blind PATRICIA trial. Clin Vaccine Immunol 2015; 22:361-73. 20. Kavanagh K, Pollock KG, Cuschieri K, et

al. Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study. Lancet Infect Dis 2017. 21. Tota JE, Struyf F, Merikukka M, et al.

Evaluation of Type Replacement Following HPV16/18 Vaccination: Pooled Analysis of Two Randomized Trials. J Natl Cancer Inst 2017; 109.

22. Woestenberg PJ, King AJ, van Benthem BHB, et al. Bivalent Vaccine Effectiveness Against Type-Specific HPV Positivity: Evidence for Cross-Protection Against Oncogenic Types Among Dutch STI Clinic Visitors. J Infect Dis 2018; 217:213-22.

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24. Mollers M, Lubbers K, Spoelstra SK, et al. Equity in human papilloma virus vaccination uptake?: sexual behaviour, knowledge and demographics in a cross-sectional study in (un)vaccinated girls in the Netherlands. BMC Public Health 2014; 14:288.

25. Rondy M, van Lier A, van de Kassteele J, Rust L, de Melker H. Determinants for HPV vaccine uptake in the Netherlands: A multilevel study. Vaccine 2010; 28:2070-5.

26. Donken R, Tami AT, Knol MJ, et al. Changes in (sexual) risk behavior and HPV knowledge in a cohort of vaccinated and unvaccinated women in the Netherlands. Manuscript in preparation.

27. Szarewski A, Skinner SR, Garland SM, et al. Efficacy of the HPV-16/18 AS04-adjuvanted vaccine against low-risk HPV types (PATRICIA randomized trial): an unexpected observation. J Infect Dis 2013; 208:1391-6.

28. Woestenberg PJ, King AJ, van der Sande MA, et al. No evidence for cross-protection of the HPV-16/18 vaccine against HPV-6/11 positivity in female STI clinic visitors. J Infect 2017; 74:393-400.

29. Howell-Jones R, Soldan K, Wetten S, et al. Declining genital Warts in young women in england associated with HPV 16/18 vaccination: an ecological study. J Infect Dis 2013; 208:1397-403.

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APPENDICES

Supplementary A. Type-specific incidence and persistence rates for high and low-risk types during

follow-up among vaccinated and unvaccinated participants of the HAVANA-study.

Incidence Unvaccinated Vaccinated

# PY n (>1 inf) Rate (1000 PY) # PY n (>1 inf) Rate (1000 PY)

hrHPV HPV16 71 3131 5 22.7 (18.0-28.6) 13 3501 0 3.7 (2.2-6.4) HPV18 37 3160 1 11.7 (8.5-16.2) 14 3497 0 4.0 (2.4-6.8) HPV31 45 3147 0 14.3 (10.7-19.2) 16 3499 1 4.6 (2.8-7.5) HPV33 22 3161 1 7.0 (4.6-10.6) 18 3497 1 5.1 (3.2-8.2) HPV35 12 3174 1 3.8 (2.1-6.7) 4 3509 0 1.1 (0.4-3.0) HPV39 43 3150 0 13.7 (10.1-18.4) 49 3477 2 14.1 (10.7-18.7) HPV45 22 3162 2 7.0 (4.6-10.6) 2 3509 0 0.6 (0.1-2.3) HPV51 116 3097 4 37.5 (31.2-44.9) 137 3417 4 40.1 (33.9-47.4) HPV52 68 3130 2 21.7 (17.1-27.6) 70 3469 1 20.2 (16.0-25.5) HPV56 56 3137 0 17.9 (13.7-23.2) 58 3473 2 16.7 (12.9-21.6) HPV58 16 3169 0 5.0 (3.1-8.2) 19 3499 1 5.4 (3.5-8.5) HPV59 19 3168 0 6.0 (3.8-9.4) 31 3489 1 8.9 (6.2-12.6) lrHPV HPV6 64 3139 1 20.4 (16.0-26.1) 55 3475 0 15.8 (12.2-20.6) HPV11 17 3173 2 5.4 (3.3-8.6) 19 3499 1 5.4 (3.5-8.5) HPV34 7 3175 0 2.2 (1.1-4.6) 7 3505 0 2.0 (1.0-4.2) HPV40 13 3174 0 4.1 (2.4-7.1) 14 3500 0 4.0 (2.4-6.8) HPV42 24 3164 0 7.6 (5.1-11.3) 30 3496 0 8.6 (6.0-12.3) HPV43 18 3168 0 5.7 (3.6-9.0) 29 3490 0 8.3 (5.8-12.0) HPV44 6 3177 0 1.9 (0.8-4.2) 9 3507 0 2.6 (1.4-4.9) HPV53 59 3138 1 18.8 (14.6-24.3) 62 3476 0 17.8 (13.9-22.9) HPV54 27 3163 1 8.5 (5.9-12.5) 38 3492 0 10.9 (7.9-15.0) HPV66 75 3132 1 24.0 (19.1-30.0) 98 3445 4 28.5 (23.3-34.7) HPV68 41 3153 0 13.0 (9.6-17.7) 36 3489 3 10.3 (7.4-14.3) HPV70 2 3179 0 0.6 (0.2-2.5) 9 3504 1 2.6 (1.3-4.9) HPV74 27 3159 1 8.5 (5.9-12.5) 30 3492 0 8.6 (6.0-12.3)

Persistence Unvaccinated Vaccinated

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lrHPV HPV11 3 3060 0 1.0 (0.3-3.0) 5 3321 0 1.5 (0.6-3.6) HPV34 0 3066 0 0.0 (0.0-1.2) 0 3324 0 0.0 (0.0-1.1) HPV40 0 3068 0 0.0 (0.0-1.2) 0 3324 0 0.0 (0.0-1.1) HPV42 4 3065 0 1.3 (0.5-3.5) 10 3315 0 3.0 (1.7-5.6) HPV43 2 3068 0 0.7 (0.2-2.6) 7 3321 0 2.1 (1.0-4.4) HPV44 3 3068 0 1.0 (0.3-3.1) 0 3324 0 0.0 (0.0-1.1) HPV53 21 3058 0 6.9 (4.5-10.5) 22 3311 0 6.6 (4.4-10.1) HPV54 6 3065 0 2.0 (0.9-4.4) 7 3318 0 2.1 (1.0-4.4) HPV66 17 3057 0 5.6 (3.5-8.9) 31 3306 1 9.4 (6.6-13.3) HPV68 6 3063 0 2.0 (0.9-4.4) 4 3320 0 1.2 (0.5-3.2) HPV70 0 3068 0 0.0 (0.0-1.2) 3 3323 0 0.9 (0.3-2.8) HPV74 7 3062 0 2.3 (1.1-4.8) 2 3323 0 0.6 (0.2-2.4)

# Total number of infections.

n(>inf) Represents the number of participants with more than one type-specific infection. PY Person-years.

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Supplementary C: Type-specific incidence and persistence rates (at least two negative rounds between

infections).

Incidence Unvaccinated Vaccinated

hrHPV HPV16 64 3011 0 21.3 (16.6-27.2) 12 3358 0 3.6 (2.0-6.3) HPV18 35 3051 0 11.5 (8.2-16.0) 14 3353 0 4.2 (2.5-7.1) HPV31 45 3040 0 14.8 (11.1-19.8) 14 3362 0 4.2 (2.5-7.0) HPV33 21 3065 1 6.9 (4.5-10.5) 17 3362 0 5.1 (3.1-8.1) HPV35 12 3083 1 3.9 (2.2-6.9) 4 3379 0 1.2 (0.4-3.2) HPV39 41 3035 0 13.5 (9.9-18.4) 42 3326 0 12.6 (9.3-17.1) HPV45 20 3066 1 6.5 (4.2-10.1) 2 3379 0 0.6 (0.1-2.4) HPV51 111 2944 1 37.7 (31.3-45.4) 125 3208 0 39.0 (21.7-46.4) HPV52 61 3007 0 20.3 (15.8-26.1) 63 3311 1 19.0 (14.9-24.4) HPV56 54 3023 0 17.9 (13.7-23.3) 56 3320 1 16.9 (13.0-21.9) HPV58 15 3073 0 4.9 (2.9-8.1) 18 3362 0 5.4 (3.4-8.5) HPV59 19 3076 0 6.2 (3.9-9.7) 26 3340 0 7.8 (5.3-11.4) lrHPV HPV6 62 3012 1 20.6 (16.1-26.4) 51 3314 0 15.4 (11.7-20.3) HPV11 14 3074 0 4.6 (2.7-7.7) 17 3357 0 5.1 (3.1-8.1) HPV34 6 3085 0 1.9 (0.9-4.3) 6 3375 0 1.8 (0.8-4.0) HPV40 13 3085 0 4.2 (2.4-7.3) 13 3364 0 3.9 (2.2-6.7) HPV42 22 3068 0 7.2 (4.7-10.9) 28 3350 0 8.4 (5.8-12.1) HPV43 18 3075 0 5.9 (3.7-9.3) 25 3346 0 7.5 (5.1-11.1) HPV44 6 3090 0 1.9 (0.9-4.3) 9 3377 0 2.7 (1.4-5.1) HPV53 55 3024 0 18.2 (14.0-23.7) 56 3314 0 16.9 (13.0-22.0) HPV54 23 3066 0 7.5 (5.0-12.9) 33 3347 0 9.9 (7.1-13.9) HPV66 72 3007 0 23.9 (19.0-30.2) 93 3253 2 28.6 (23.3-35.0) HPV68 38 3039 0 12.5 (9.1-17.2) 31 3339 1 9.3 (6.5-13.2) HPV70 2 3092 0 0.6 (0.2-2.6) 8 3372 0 2.4 (1.2-4.7) HPV74 24 3054 0 7.9 (5.3-11.7) 27 3348 0 8.1 (5.5-11.8)

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2

lrHPV HPV42 4 2959 0 1.4 (0.5-3.6) 10 3195 0 1.0 (1.7-5.8) HPV43 2 2962 0 0.7 (0.2-2.7) 6 3202 0 1.9 (0.8-4.2) HPV44 3 2962 0 1.0 (0.3-3.1) 0 3204 0 0.0 (0.0-1.2) HPV53 19 2952 0 6.4 (4.1-10.1) 20 3192 0 6.3 (4.0-9.7) HPV54 5 2959 0 1.7 (0.7-4.1) 6 3199 0 1.9 (0.8-4.2) HPV66 17 2951 0 5.8 (3.6-9.3) 30 3187 0 9.4 (6.6-13.4) HPV68 6 2957 0 2.0 (0.9-4.5) 3 3201 0 0.9 (0.3-2.9) HPV70 0 2962 0 0.0 (0.0-1.2) 2 3203 0 0.6 (0.2-2.5) HPV74 7 2956 0 2.4 (1.1-5.0) 2 3203 0 0.6 (0.2-2.5)

# Total number of infections.

n(>inf) Represents the number of participants with more than one type-specific infection. PY Person-years.