Background More than ten years have elapsed since human papillomavirus (HPV) vaccination was implemented. We performed a systematic review and meta-analysis of the population-level impact of female-only HPV vaccination on HPV infections, anogenital wart diagnoses (AGW) 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 We updated our prior review (01/01/2007-28/02/2014), by searching Medline and Embase (01/02/2014-11/10/2018) for studies that examined changes, between pre-and post-vaccination periods, in HPV infections, AGW, or CIN2+. We stratified all analyses by sex, age, and years since HPV vaccination introduction. We used random-effects models to estimate pooled relative risks and performed subgroup analysis to identify the main sources of heterogeneity. Findings We identified 65 eligible articles conducted in 14 high-income countries. After 5-8 years of vaccination, HPV-16/18, AGW, and CIN2+ decreased significantly by about 80%, 70%, and 50% among girls aged 15-19 years and by 65%, 55%, and 30% among women aged 20-24 years. Significant cross-protection and herd effects were also observed. HPV-31/33/45 decreased significantly by 50% among girls aged 15-19 years and AGW decreased significantly by 30-50% among boys/men aged 15-24 years. After 5-8 years of vaccination, countries with multi-cohort vaccination and high coverage (≥50%) had greater reductions in AGW, 44 and 85 percentage points among girls and boys aged 15-19 years, respectively, than countries with single-cohort vaccination and/or low vaccination coverage. Interpretation Our meta-analysis, including data from >60 million individuals from 14 high-income countries, shows a substantial impact of female-only HPV vaccination programs on AGW among girls/women and boys/men, and HPV infections and CIN2+ among girls/women. In addition, programs with multi-cohort vaccination and high vaccination coverage lead to greater and faster direct impact and herd effects. CONTRIBUTIONS MD, MB, and MCB conceived the study. MD, EB and NP did the literature search and performed the analysis. MB and MCB participated in the analysis. MD and MB co-drafted the first version of the article.

Human papillomavirus (HPV) types 16/18, included in HPV vaccines, contribute to the majority of cervical cancer, and a substantial proportion of cervical intraepithelial neoplasia (CIN) grades 2/3 or worse (CIN2+/CIN3+) including adenocarcinoma in situ or worse. The aim of this study was to quantify the effect of quadrivalent HPV (qHPV) vaccination on incidence of CIN2+ and CIN3+. A nationwide cohort of girls and young women resident in Sweden 2006–2013 and aged 13–29 (n = 1,333,691) was followed for vaccination and histologically confirmed high‐grade cervical lesions. Data were collected using the Swedish nationwide healthcare registers. Poisson regression was used to calculate incidence rate ratios (IRRs) and vaccine effectiveness [(1‐IRR)x100%] comparing fully vaccinated with unvaccinated individuals. IRRs were adjusted for attained age and parental education, and stratified on vaccination initiation age. Effectiveness against CIN2+ was 75% (IRR = 0.25, 95%CI = 0.18–0.35) for those initiating vaccination before age 17, and 46% (IRR = 0.54, 95%CI = 0.46–0.64) and 22% (IRR = 0.78, 95%CI = 0.65–0.93) for those initiating vaccination at ages 17–19, and at ages 20–29, respectively. Vaccine effectiveness against CIN3+ was similar to vaccine effectiveness against CIN2+. Results were robust for both women participating to the organized screening program and for women at prescreening ages. We show high effectiveness of qHPV vaccination on CIN2+ and CIN3+ lesions, with greater effectiveness observed in girls younger at vaccination initiation. Continued monitoring of impact of HPV vaccination in the population is needed in order to evaluate both long‐term vaccine effectiveness and to evaluate whether the vaccination program achieves anticipated effects in prevention of invasive cervical cancer.

BackgroundIncidence of condyloma, or genital warts (GW), is the earliest possible disease outcome to measure when assessing the effectiveness of human papillomavirus (HPV) vaccination strategies. Efficacy trials that follow prespecified inclusion and exclusion criteria may not be fully generalizable to real-life HPV vaccination programs, which target a broader segment of the population. We assessed GW incidence after on-demand vaccination with quadrivalent HPV vaccine using individual-level data from the entire Swedish population.MethodsAn open cohort of girls and women aged 10 to 44 years living in Sweden between 2006 and 2010 (N > 2.2 million) was linked to multiple population registers to identify incident GW in relation to HPV vaccination. For vaccine effectiveness, incidence rate ratios of GW were estimated using time-to-event analyses with adjustment for attained age and parental education level, stratifying on age at first vaccination.ResultsA total of 124 000 girls and women were vaccinated between 2006 and 2010. Girls and women with at least one university-educated parent were 15 times more likely to be vaccinated before age 20 years than girls and women whose parents did not complete high school (relative risk ratio = 15.45, 95% confidence interval [CI] = 14.65 to 16.30). Among those aged older than 20 years, GW rates declined among the unvaccinated, suggesting that HPV vaccines were preferentially used by women at high risk of GW. Vaccination effectiveness was 76% (95% CI = 73% to 79%) among those who received three doses of the vaccine with their first dose before age 20 years. Vaccine effectiveness was highest in girls vaccinated before age 14 years (effectiveness = 93%, 95% CI = 73% to 98%).ConclusionsYoung age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness.

Although maximum reduction in condyloma risk was seen after receipt of 3 doses of quadrivalent HPV vaccine, receipt of 2 vaccine doses was also associated with a considerable reduction in condyloma risk. The implications of these findings for the relationship between number of vaccine doses and cervical cancer risk require further investigation.

This study provides a reasonable estimation of the incidence of GW in the Swedish population by use of register data, with results comparable to those from previous smaller studies. There was a downward trend of GW incidence among younger females between 2006 and 2010.