The effectiveness of HPV vaccination against invasive cervical cancer and related precancerous lesions: a multinational target trial emulation study
Menée à l'aide de données du Royaume-Uni, de Norvège et d'Espagne portant sur 244 962 femmes vaccinées contre le papillomavirus humain (HPV) et 90 382 femmes non vaccinées, cette émulation d'essai cible estime l’efficacité de la vaccination contre le HPV pour la prévention des lésions précancéreuses de haut grade et du cancer invasif du col de l’utérus
Background: Human Papillomavirus (HPV) vaccines prevent HPV infection and related disease. 15 years after the first HPV vaccination programmes were launched in Europe, their long-term effectiveness can now start to be assessed. We designed a target trial emulation study to estimate the effectiveness of HPV vaccination in preventing invasive cervical cancer and high-grade precancerous lesions using three primary care databases.
Methods: In this target trial emulation study, we analysed primary care records from the UK (Clinical Practice Research Datalink; data from Sept 9, 1987 to Dec 15, 2023), primary care records linked to hospital records from Catalonia, Spain (Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària; Jan 1, 2006 to June 30, 2023), and nationwide linked health registry (including primary care, secondary care, and other health data) in Norway (Norwegian Linked Health Registry; Jan 1, 2018 to Dec 31, 2023), all standardised to the Observational Medical Outcomes Partnership common data model. We included women aged 15 years or younger in 2008, coinciding with the start of public vaccination programmes. Exposure was defined as receiving one or more HPV vaccine doses by age 15 years. The main outcomes included high-grade cervical intraepithelial neoplasia (CIN2+), invasive cervical cancer, and conisation (as a proxy for CIN2+ diagnosis). Vaccinated and unvaccinated cohorts were sequentially matched on an annual basis by year of birth, location, and propensity scores, with up to five vaccinated people matched to an unvaccinated individual. Vaccine effectiveness, based on incidence rate ratios after 15 years of follow-up, were calculated using Poisson regression. Results across databases were meta-analysed using fixed-effects. The specified primary analysis in the original protocol was designed to assess exposure by HPV brand versus unvaccinated populations; however, due to the low number of events by brand, the study was underpowered and the primary analysis was amended to assess HPV vaccination exposure overall (any brand) versus unvaccinated.
Findings: After two-step matching, our analysis included 81 863 vaccinated and 46 357 unvaccinated women from the UK; 148 214 vaccinated and 39 952 unvaccinated from Spain; and 14 885 vaccinated and 4073 unvaccinated from Norway. Fewer than five cervical cancers were observed per cohort, precluding vaccine effectiveness estimation for this outcome. Meta-analytic vaccine effectiveness at 15 years was 42% (95% CI 6–64) against CIN2+ and 58% (6–82) against conisation.
Interpretation: Our estimates of vaccine effectiveness against CIN2+ and conisation in Europe align with estimates from previous systematic reviews of randomised controlled trials. We also observed an increased health-seeking behaviour among vaccinated individuals, suggesting that our study might have underestimated vaccine effectiveness. Further studies with longer follow-up are needed to estimate vaccine effectiveness against cervical cancer.
The Lancet Primary Care , article en libre accès, 2026