Articles
Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study

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Summary

Background

On Sept 1, 2008, Scotland launched routine vaccination for human papillomavirus (HPV) types 16 and 18, targeted at 12–13-year-old girls, of whom 92·4% were fully vaccinated in 2008–09. In this study, we report on vaccine effectiveness of the bivalent vaccine in these vaccinated women who attended for routine cervical screening at age 20–21 years.

Methods

In this 7-year cross-sectional study (covering birth cohorts 1988–1995), we sampled approximately 1000 samples per year from those attending cervical screening at age 20–21 years and tested each for HPV. By linkage to vaccination records we ascertained prevalence by birth cohort and vaccination status. Estimates of vaccine effectiveness for HPV types 16 and 18, HPV types 31, 33, and 45, other high-risk types, and any HPV were calculated using logistic regression.

Findings

In total, 8584 samples were HPV genotyped. Prevalence of HPV types 16 and 18 reduced substantially from 30·0% (95% CI 26·9–33·1) in the 1988 cohort to 4·5% (3·5–5·7) in the 1995 cohort, giving a vaccine effectiveness of 89·1% (85·1–92·3) for those vaccinated at age 12–13 years. All cross-protective types showed significant vaccine effectiveness (HPV type 31, 93·8% [95% CI 83·8–98·5]; HPV type 33, 79·1% [64·2–89·0]; HPV type 45, 82·6% [61·5–93·9]). Unvaccinated individuals born in 1995 had a reduced odds of HPV types 16 and 18 infection compared with those born in 1988 (adjusted odds ratio 0·13 [95% CI 0·06–0·28]) and reduced odds of HPV types 31, 33, and 45 (odds ratio 0·45 [0·23–0·89]).

Interpretation

Bivalent vaccination has led to a startling reduction in vaccine and cross-protective HPV types 7 years after vaccination. There is also evidence of herd protection against the vaccine-specific and cross-protective types in unvaccinated individuals born in 1995. These findings should be considered in cost-effectiveness models informing vaccine choice and models to shape the future of cervical screening programmes.

Funding

Scottish Government and Chief Scientists Office.

Introduction

Human papillomavirus (HPV) types 16 and 18 are responsible for 70–80% of cervical cancers in the UK.1 HPV vaccination prevents infection with HPV types 16 and 182, 3, 4 and is associated with a reduction in all grades of histological and cytological abnormalities according to data from population-based immunisation programmes.5, 6 The bivalent vaccine also provides immunological cross-protection against HPV types 31, 33, and 45, which are high-risk oncogenic types phylogenetically related to types 16 and 18, although the duration and scale of long-term cross-protective immunity has been vigorously debated.3, 7, 8, 9 Cross-reactive antibodies against HPV 31 and 45 can persist for up to 9·4 years after bivalent HPV vaccination in clinical trials.10 These data are particularly relevant for Scotland since at least 90% of invasive cervical cancers are attributable to HPV types 16, 18, 31, 33, or 45.11

To date, data on the impact of HPV vaccine2, 3, 4, 7, 12 through national vaccination programmes are largely obtained from females immunised as part of catch-up cohorts which, in Scotland, included girls up to age 18 years. Although data derived from catch-up populations have been encouraging, they are likely to underestimate the effect as some recipients will have been exposed to HPV before vaccination. Cervical screening programmes mostly screen from age 25 years or older. Assessment of vaccine impact before entering cervical screening programmes has been possible either ecologically by testing for HPV in higher risk populations attending chlamydia screening13, 14, 15 or via national surveys16 reliant on self-reported vaccine status and self-collected samples. So far, there have been limited opportunities to observe changes in prevalence in women routinely vaccinated at ages 12 or 13 years.

Until June 1, 2016, cervical screening started at age 20 years in Scotland. Therefore, using the ability to link individual screening and vaccination records, we can report on effectiveness of the bivalent vaccine on both low-risk and high-risk HPV infections in girls aged 12–13 years, of whom 92·4% were fully vaccinated in 2008–09.17 Timely production and analyses of these data have substantial implications for service planning and cost-effectiveness modelling to inform future cervical disease prevention policy.

Research in context

Evidence before this study

Two systematic reviews and meta-analyses have collated population-based data demonstrating early evidence of the effectiveness of the human papillomavirus (HPV) vaccination programme in high-income countries. These studies showed a significant reduction in HPV type 16 and 18 associated with the vaccine. Although reduction in HPV types 31 was suggested, there was no evidence of a reduction in HPV types 31, 33 and 45 as a group. Studies included in these reviews covered both the bivalent and quadrivalent vaccines, had differing levels of vaccine uptake, were often ecological studies comparing prevalence in different timeframes, and were focused on those vaccinated at older ages as part of catch-up cohorts.

On March 8, 2016, we did a PubMed search using the terms (“papillomavirus vaccine”, “papillomavirus vaccination”, “HPV vaccine”, or “HPV vaccination”) and (“program evaluation”, “population surveillance”, “sentinel surveillance”, “incidence”, or “prevalence”), with 151 articles published in the intervening period since the 2015 review paper (from Feb 1, 2014, to March 8, 2016), and found a further six studies, including our own work, reporting population-based HPV prevalence in vaccinated populations from England, Scotland, Sweden, Australia, and the USA (two studies) with all except the UK studies evaluating the impact of the quadrivalent vaccine. The populations studied were generally vaccinated during catch-up campaigns and were attending cervical screening at age 25 years or older, or were vaccinated at an earlier age and observed as part of screening high-risk populations or through national surveys using self-collected samples. For most studies, individual vaccination status was not known; rather, changes in the prevalence of HPV before and after vaccination were examined. No studies have presented population-based evidence for those vaccinated at age 12 or 13 years where vaccine status is known. With the exception of our own work, no statistically significant evidence of vaccine effectiveness for the grouping of the cross-protective types was found in the aforementioned studies.

Added value of this study

This study is the first to present population-based evidence of the effectiveness of the bivalent HPV vaccine in girls vaccinated routinely at age 12 or 13 years and attending for cervical screening at age 20 years. We have shown that the vaccine-specific types (HPV types 16 and 18) and the cross-protective types (HPV types 31, 33, and 45) have almost disappeared in this population, 7 years following the receipt of vaccine, and present evidence of herd protection for all these types. We also demonstrate significant vaccine effect for the cross-protective types individually.

Implications of all the available evidence

These reductions in the most carcinogenic types of HPV, which are implicated in 90% of cervical cancers in Scotland, will reduce the predictive value of cytology and HPV-based screening strategies, which could affect their cost-effectiveness. Defining optimal screening intervals, age range, test, and triage strategies for vaccinated women should be investigated. Our findings should inform the evaluation of screening programmes in vaccinated populations with high levels of uptake. Additionally, the effectiveness of the vaccine observed, particularly for cross-protective types, might affect the comparative cost-effectiveness of the bivalent, quadrivalent, and nonavalent HPV vaccines and our findings should be incorporated in the baseline assumptions of such evaluative models. If the cross-protection of the bivalent vaccine improves cost-effectiveness then the bivalent vaccine remains a strong candidate for consideration in HPV immunisation programmes.

Section snippets

Study design and setting

In this 7-year cross-sectional study we estimated HPV vaccine effectiveness in those vaccinated as part of both routine and catch-up immunisation programmes in Scotland. On Sept 1, 2008, Scotland began school-based routine HPV vaccination, targeted at girls aged 12–13 years. Between Sept 1, 2008, and Aug 31, 2011, a 3-year catch-up programme for older girls (aged 13–18 years, born between Sept 1, 1990, and Aug 31, 1995) was also delivered, both at school and, for school leavers, at Health

Results

Over the 7 years of surveillance, 8708 liquid-based cytology samples were collected. 61 entries were excluded as SIMD quintile could not be linked and a further 63 could not be HPV genotyped. The remaining 8584 samples were successfully HPV genotyped and formed the study population. Breakdown by year is shown in appendix (p 1). In the 2009 collection year, individuals attending for first smear born in 1988 and 1989 were not eligible for routine vaccination, hence 98·5% (1631 of 1656) were

Discussion

Population-based data from the Scottish HPV immunisation programme clearly show that the bivalent vaccine is associated with a significant reduction in the prevalence of HPV types 16 and 18 and each of the cross-protective types 31, 33, and 45 in women attending routine cervical screening. The magnitude of this effect increases with successive birth cohorts. Moreover, we show that cross-protection remains high at age 20 years for girls vaccinated at age 12–13 years, differing from an earlier

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