Summary Background Human papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations. Methods We searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random-effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I2 and χ2 statistics and we did trends analysis to examine the dose–response association between HPV vaccination coverage and each study effect measure. Findings We identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow-up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post-vaccination periods by 68% (RR 0·32, 95% CI 0·19–0·52) and anogenital warts decreased significantly by 61% (0·39, 0·22–0·71) in girls 13–19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0·72, 95% CI 0·54–0·96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0·66 [95% CI 0·47–0·91]) and in women 20–39 years of age (0·68 [95% CI 0·51–0·89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0·50, 95% CI 0·34–0·74]) and in anogenital warts (0·86 [95% CI 0·79–0·94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects. Interpretation Our results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement. Funding The Canadian Institutes of Health Research.

Two-dose HPV vaccination is likely to be cost-effective if its duration of protection is at least 10 years. A third dose of HPV vaccine is unlikely to be cost-effective if two-dose duration of protection is longer than 30 years. Finally, two-dose girls & boys HPV vaccination is unlikely to be cost-effective unless the cost per dose for boys is substantially lower than the cost for girls.

The clustering of human papillomavirus (HPV) infections in some individuals is often interpreted as the result of common risk factors rather than biological interactions between different types of HPV. The intraindividual correlation between times-at-risk for all HPV infections is not generally considered in the analysis of epidemiologic studies. We used a deterministic transmission model to simulate cross-sectional and prospective epidemiologic studies measuring associations between 2 HPV types. When we assumed no interactions, the model predicted that studies would estimate odds ratios and incidence rate ratios greater than 1 between HPV types even after complete adjustment for sexual behavior. We demonstrated that this residual association is due to correlation between the times-at-risk for different HPV types, where individuals become concurrently at risk for all of their partners' HPV types when they enter a partnership and are not at risk when they are single. This correlation can be controlled in prospective studies by restricting analyses to susceptible individuals with an infected sexual partner. The bias in the measured associations was largest in low-sexual-activity populations, cross-sectional studies, and studies which evaluated infection with a first HPV type as the exposure. These results suggest that current epidemiologic evidence does not preclude the existence of competitive biological interactions between HPV types.