Elsevier

The Lancet

Volume 394, Issue 10197, 10–16 August 2019, Pages 497-509
The Lancet

Articles
Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(19)30298-3Get rights and content

Summary

Background

More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+) to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination.

Methods

In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks.

Findings

We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+. After 5–8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0·17, 95% CI 0·11–0·25) among girls aged 13–19 years, and decreased significantly by 66% (RR 0·34, 95% CI 0·23–0·49) among women aged 20–24 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0·46, 95% CI 0·33–0·66) among girls aged 13–19 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0·33, 95% CI 0·24–0·46) among girls aged 15–19 years, decreased significantly by 54% (RR 0·46, 95% CI 0.36–0.60) among women aged 20–24 years, and decreased significantly by 31% (RR 0·69, 95% CI 0·53–0·89) among women aged 25–29 years. Among boys aged 15–19 years anogenital wart diagnoses decreased significantly by 48% (RR 0·52, 95% CI 0·37–0·75) and among men aged 20–24 years they decreased significantly by 32% (RR 0·68, 95% CI 0·47–0·98). After 5–9 years of vaccination, CIN2+ decreased significantly by 51% (RR 0·49, 95% CI 0·42–0·58) among screened girls aged 15–19 years and decreased significantly by 31% (RR 0·69, 95% CI 0·57–0·84) among women aged 20–24 years.

Interpretation

This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects.

Funding

WHO, Canadian Institutes of Health Research, Fonds de recherche du Québec – Santé.

Introduction

More than 10 years after the licensure of the first human papillomavirus (HPV) vaccines, 99 countries and territories have introduced HPV vaccination programmes.1, 2 Observational data showing the population-level impact of HPV vaccination from the early adopting countries can be immensely useful for decision makers examining whether to introduce or modify HPV vaccination programmes. This is because such data show the effectiveness of HPV vaccines in real-world settings and can assist in the identification of programme characteristics that lead to the greatest reductions in HPV-related infections and diseases.

In 2015, we did a systematic review and meta-analysis of the population-level impact of HPV vaccination, including data from nine high-income countries up to 4 years after the introduction of HPV vaccination.3 Our meta-analysis showed substantial decreases in HPV 16 and 18 infections and anogenital wart diagnoses among girls and young women targeted for vaccination. Furthermore, in countries with high vaccination coverage (≥ 50%) there was evidence of vaccine cross-protection and herd effects, with significant reductions in HPV 31, 33, and 45 infections among girls targeted for vaccination and anogenital wart diagnoses among unvaccinated boys and older women. However, in our meta-analysis of 2015, the number of years after vaccination was insufficient to examine the impact of HPV vaccination on the occurrence of cervical intraepithelial neoplasia grade 2+ (CIN2+). CIN2+ may take several years to develop, and is the most proximal outcome for cervical cancer.4

Research in context

Evidence before this study

Since 2007, 99 countries and territories have introduced human papillomavirus (HPV) vaccination programmes. In 2015, we did a systematic review and meta-analysis to examine the real-world population-level impact of HPV vaccination. The meta-analysis showed substantial decreases in HPV 16 and HPV 18 infections and anogenital wart diagnoses among women targeted for vaccination, and evidence of herd effects among boys and older women, 4 years after the introduction of HPV vaccination. However, at the time of the meta-analysis, the number of years post-vaccination was insufficient to examine the impact of HPV vaccination on cervical intraepithelial neoplasia grade 2+ (CIN2+). Moreover, in 2016, the WHO Strategic Advisory Group of Experts on Immunization revised its position to recommend HPV vaccination of multiple age cohorts of girls, rather than vaccination of a single cohort.

We updated our previous systematic review and meta-analysis to: (1) update and summarise the most recent evidence about the population-level impact of girls-only HPV vaccination on HPV infections and anogenital wart diagnoses among girls, boys, women, and men; (2) summarise new evidence about the population-level impact of girls-only HPV vaccination on CIN2+ occurrence among screened girls and women; and (3) compare the population-level impact of HPV vaccination on anogenital wart diagnoses and CIN2+ occurrence between countries that have implemented either a single or a multiple age-cohort vaccination strategy. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018, with the same combination of MeSH terms, title, or abstract words: (“papillomavirus vaccine”, “papillomavirus vaccination”, “HPV vaccine”, or “HPV vaccination”) and (“program evaluation”, “population surveillance”, “sentinel surveillance”, “incidence”, or “prevalence”), and (“papillomavirus infection”, “condylomata acuminata”, “anogenital warts”, “cervical intraepithelial neoplasia”, “cervical dysplasia”, “uterine cervical neoplasm”, or “HPV related diseases”). We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+. We contacted all corresponding authors of eligible studies to request a re-analysis of their data using the same data stratification to allow comparison between studies and pooling.

Added value of this study

The current updated systematic review and meta-analysis, which includes data from 60 million individuals and up to 8 years of post-vaccination follow-up, shows compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections, anogenital wart diagnoses, and CIN2+ among women, and herd effects among boys and older women. Our study also shows greater and faster direct impact and herd effects in countries with multiple age-cohort vaccination and high vaccination coverage, compared with countries with single age-cohort vaccination or low routine vaccination coverage. To our knowledge, our study is the first to present pooled estimates of the population-level impact of HPV vaccination on CIN2+ (the most proximal outcome to cervical cancer), and the first to show the real-world additional benefit of vaccinating multiple age cohorts of girls with high vaccination coverage.

Implications of all the available evidence

Our results provide strong evidence of HPV vaccination working to prevent cervical cancer in real-world settings, as both the cause (high-risk HPV infection) and proximal disease endpoint (CIN2+) are significantly declining. In terms of global policy implications, these results reinforce the recently revised position of WHO recommending HPV vaccination of multiple age cohorts of girls, and provide promising early signs that the WHO call for action on cervical cancer elimination might be possible if sufficient population-level vaccination coverage can be reached.

We wanted to update our systematic review and meta-analysis for three main reasons. First, the number of countries and studies reporting observational data of the population-level impact of HPV vaccination has increased dramatically since our first review, which will improve both the power and generalisability of the results. Second, the number of years after vaccination has increased, which allows analysis of changes in CIN2+ since the introduction of HPV vaccination. Finally, the WHO Strategic Advisory Group of Experts on Immunization revised its position in 2016 to recommend HPV vaccination of multiple age cohorts of girls (9–14 years old) when the vaccine is introduced in a country, rather than vaccination of a single age cohort.5 Before this recommendation, some high-income countries had implemented vaccination of multiple age cohorts, mainly through catch-up campaigns. A better understanding of the population-level impact of will help inform decisions of policy makers regarding the recent WHO recommendations.

Thus, the aims of this systematic review and meta-analysis are to: (1) update and summarise the most recent evidence about the population-level impact of girls-only HPV vaccination on HPV infections and anogenital wart diagnoses among girls, boys, women, and men; (2) summarise new evidence about the population-level impact of girls-only HPV vaccination on CIN2+ occurrence among screened girls and women; and (3) compare the population-level impact of HPV vaccination on anogenital wart diagnoses and CIN2+ occurrence between countries that have implemented either a single or a multiple age-cohort vaccination strategy.

Section snippets

Search strategy and selection criteria

In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper3 and report our methods in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines (appendix pp 4–5).6 Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and

Results

We identified 1702 potentially eligible articles, and included 65 articles (from 40 studies) in this systematic review and meta-analysis: 23 for HPV infection,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 29 for anogenital warts,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 and 13 for CIN2+ (figure 1).65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 The studies were done in 14

Discussion

This systematic review and meta-analysis, including data from 14 high-income countries, shows a significant and substantial impact of HPV vaccination on three HPV-related endpoints in the first 9 years after the start of HPV vaccination. Over this period, HPV 16 and 18 infections, anogenital wart diagnoses, and CIN2+ decreased significantly among girls and women. There was also evidence of vaccine cross-protection (HPV 31, 33, and 45 decreased significantly among girls younger than 20 years)

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