Real-world Impact of HPV Vaccination on CIN2+ Reduction: A Meta-analysis of Observational Studies Assessing Variation by Age, Coverage, and Vaccine Type.

Background: Human papillomavirus (HPV) vaccination reduces the incidence of high-grade cervical lesions, but its population-level impact on cervical intraepithelial neoplasia grade 2 or worse (CIN2+) may vary by age at vaccination, program coverage, and vaccine type. The extent to which these factors explain variation in CIN2+ outcomes across real-world vaccination programs remains incompletely quantified. Methods: Using data from a prior systematic review of observational studies across HPV-related endpoints, we restricted this meta-analysis to studies reporting histologically confirmed CIN2+. Reported ratio measures were analyzed on the natural log scale using random-effects models fitted by restricted maximum likelihood with Hartung-Knapp-Sidik-Jonkman inference. Prespecified subgroup analyses examined age at vaccination, vaccination coverage, and vaccine type. Exploratory univariable meta-regressions assessed follow-up duration, age-at-vaccination category, study design, and publication year. Sensitivity analyses evaluated the influence of effect-measure type, alternative between-study variance estimation, and trim-and-fill adjustment. A frequentist network meta-analysis (NMA) compared vaccine types versus no vaccination. Results: Twenty-two studies were included. HPV vaccination was associated with a pooled ratio estimate of 0.38 (95% CI 0.29-0.50), corresponding to an approximate 62% reduction in CIN2+ occurrence. Heterogeneity was very high (I Conclusions: HPV vaccination was associated with a substantial average reduction in CIN2+ occurrence across observational studies. However, high heterogeneity, wide prediction intervals, nonsignificant subgroup tests, and indirect network comparisons indicate that subgroup and vaccine-type findings should be interpreted cautiously.