Volume 1, Issue 1, November 2016, Pages e8–e17

Open Access
Articles

Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: a systematic review and meta-analysis of predictions from transmission-dynamic models

  • a Centre de recherche du CHU de Québec—Université Laval, Quebec City, QC, Canada
  • b Département de médecine sociale et préventive, Université Laval, Quebec City, QC, Canada
  • c Department of Infectious Disease Epidemiology, Imperial College, London, UK
  • d Centre for Infectious Disease Control, National Institute of Public Health and the Environment, Bilthoven, Netherlands
  • e Infection and Cancer Epidemiology Group, International Agency for Research on Cancer, Lyon, France
  • f Unit of Cancer Epidemiology, Department of Medical Sciences, University of Turin, Turin, Italy
  • g Vaccination Programme Unit, National Institute for Health and Welfare, Helsinki, Finland
  • h Modelling and Economics Unit, Public Health England, London, UK
  • i Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
  • j Cancer Research Division, Cancer Council NSW, Sydney, NSW, Australia
  • k Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands
  • l Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
  • m Division of STD Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
  • n Center for Health Decision Science, Harvard T H Chan School of Public Health, Boston, MA, USA
  • o Department of Global Health and Population, Harvard T H Chan School of Public Health, Boston, MA, USA
  • p Department of Health Management and Health Economics, University of Oslo, Oslo, Norway
  • q National Infection Service, Public Health England, London, UK
  • r Oslo Centre for Biostatistics and Epidemiology, Division of Infectious Disease Control, Norwegian Institute of Public Health and Oslo Centre for Statistics and Epidemiology, Oslo, Norway
  • s Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
  • t Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
  • u Fondazione Bruno Kessler, Trento, Italy
  • v Epidemiological and Statistical Methods Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
  • w Section for Geography, Department of Geosciences and Natural Resource Management, University of Copenhagen, Copenhagen, Denmark
  • x Merck Research Laboratories, Rahway, NJ, USA
  • y Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
  • z National Centre for Pharmacoeconomics (NCPE Ireland), Dublin, Ireland
  • aa Department of Mathematics and Statistics, University of Limerick, Limerick, Ireland

Summary

Background

Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination.

Methods

We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% efficacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine efficacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RRprev) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals [UI]).

Findings

16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RRprev of HPV 16 among women and men was 0·53 (80% UI 0·46–0·68) and 0·36 (0·28–0·61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RRprev of HPV 16 among women and men was 0·93 (0·90–1·00) and 0·83 (0·75–1·00), respectively. Vaccinating boys in addition to girls increased the RRprev of HPV 16 among women and men by 0·18 (0·13–0·32) and 0·35 (0·27–0·39) for 40% coverage, and 0·07 (0·00–0·10) and 0·16 (0·01–0·25) for 80% coverage, respectively. The RRprev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RRprev of 1·00 for women and men for all four HPV types. Variability in pooled findings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years).

Interpretation

Although HPV models differ in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd effects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine efficacy is maintained over time.

Funding

Canadian Institutes of Health Research.


Introduction

Since 2006, two prophylactic human papillomavirus (HPV) vaccines have been widely used worldwide: the bivalent and quadrivalent vaccines. Both vaccines target HPV 16 and 18, which cause about 50% of high-grade cervical lesions, 70% of cervical cancers, and 40–80% of other HPV-related cancers.1, 2, 3, 4 and 5 The quadrivalent vaccine also targets HPV 6 and 11, which are associated with 80–90% of anogenital wart cases.6 Large randomised controlled clinical trials have shown that both vaccines are highly effective in protecting against vaccine-type persistent HPV infection and precancerous lesions in women and men (vaccine efficacy 93–100%).7 and 8 More than 65 countries have introduced HPV vaccination programmes.9 and 10 Most programmes target girls only, with only a handful of countries vaccinating both girls and boys (eg, the USA, Australia, Switzerland, Austria, and Canada).11, 12, 13, 14, 15, 16 and 17 These decisions have been made with substantial input from mathematical models.11, 18, 19, 20, 21 and 22 Recently, a nonavalent vaccine, which targets HPV 31, 33, 45, 52, and 58 also, has been licensed and recommended for use in the USA23 after reports of strong efficacy and immunogenicity from large trials.24

Research in context

Evidence before this study

Many models have been developed over the past decade to understand HPV epidemiology and to help guide policy decisions concerning HPV vaccination. However, it is unknown whether these models are giving consistent results in terms of HPV vaccination population-level effectiveness, herd effects, incremental benefit of vaccinating boys in addition to girls, and elimination. To examine this question, we conducted a systematic review and meta-analysis of HPV transmission-dynamic model predictions of the long-term population-level effectiveness of HPV vaccination against HPV 6, 11, 16, and 18 infection in women and men. To our knowledge, this is the first meta-analysis of HPV model predictions, and is the first to examine the potential for elimination.

Added value of the study

Our study shows that the HPV models give generally consistent results, which can be reassuring for decision makers using these models for vaccination policy decisions. Results suggest that HPV vaccination will produce strong herd effects leading to substantial long-term reductions in HPV infection and related diseases in unimmunised women and men. Herd effects are predicted even with vaccination coverage as low as 20%. Given the substantial herd effects of girls-only vaccination when coverage is moderate to high, the incremental benefit of vaccinating boys is predicted to be small. To our knowledge, our study is the first to suggest that elimination of vaccine-targeted HPV types is possible if vaccination coverage of girls and boys reaches 80%. Finally, our study includes a greater number of models than any published comparison of infectious disease models, reflecting the influential role modelling has played in HPV vaccination policy decisions.

Implications of available evidence

HPV vaccination is likely to have a strong direct and indirect impact across different countries and coverage levels. The case for vaccinating boys could mainly depend on other issues besides the predicted additional benefit for heterosexual males, such as cost of the vaccine for boys, feasibility of increasing coverage in girls, and equity for men who have sex with men. Although early post-HPV vaccination surveillance data do not show herd effects in settings with low coverage, our study suggests that this is probably because herd effects take longer to become evident when coverage is lower. Policy makers might want to examine whether to set objectives to eliminate HPV vaccine types in their jurisdictions.

Mathematical models have consistently predicted that vaccinating girls against HPV is highly cost-effective,25, 26 and 27 however, the picture is less clear for vaccinating boys.28, 29, 30, 31, 32, 33, 34 and 35 This is because the cost-effectiveness of vaccinating girls is mainly driven by the direct benefit of HPV vaccination among vaccinated women, which depends on well quantified parameters such as vaccine efficacy and the proportion of cervical cancer due to the vaccine types.27 The incremental effectiveness and cost-effectiveness of vaccinating boys is influenced largely by the magnitude of indirect protection conferred to men by vaccinating girls (herd immunity), which depends on a complex combination of factors (eg, vaccination coverage and sexual behaviour).28, 35 and 36 Modelling studies have shown that if vaccinating girls significantly reduces the burden of HPV-related diseases in men through herd immunity, then vaccinating boys will produce limited additional population-level benefits for heterosexual men and women and thus will not be cost-effective at the same vaccine price.28, 30 and 35 However, it is unclear what vaccination coverage is necessary to achieve substantial herd effects, and whether models are consistent in their predictions.

A systematic review of population-level HPV post-vaccination surveillance data has shown significant reductions in anogenital warts in young men in the first 4 years after girls-only quadrivalent vaccination programmes with high coverage (≥50%).37 In countries with low vaccination coverage (<50%) there was no indication of herd effects.37 In Australia, where quadrivalent vaccination coverage among girls has been consistently higher than 70%, anogenital warts consultations among heterosexual men declined by more than 80% within the first 5 years of the programme (before vaccination of boys).38 These results suggest that HPV vaccination can produce important herd effects for the anogenital warts associated types (HPV 6 and 11), and that elimination of these types might be achievable.

Better understanding the potential long-term population-level effectiveness of HPV vaccination, including herd effects, is crucial to help inform future vaccine policy decisions such as the inclusion of boys in vaccination programmes, incremental impact of increasing vaccination coverage and optimal combinations of HPV vaccination and cervical cancer screening strategies. Mathematical models provide a formal framework to examine these questions, which cannot be answered in trial settings. However, models require many assumptions, which might lead to questions about the validity of predictions and uncertainty for decision makers. A large number of HPV models have been developed over the past decade, but it is still unclear whether the models are giving consistent results and whether we can draw general principles from them. We conducted a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of HPV vaccination against HPV 6, 11, 16, and 18 infection in women and men, to examine the robustness and variability of predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV vaccine-type elimination.