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 (I2 = 97.0%), and the 95% prediction interval crossed 1 (0.12-1.23), indicating substantial variation in expected effects across real-world vaccination programs. Point estimates were generally protective across subgroup strata, but subgroup differences by age at vaccination, vaccination coverage, and vaccine type were not statistically significant. Sensitivity analyses were directionally consistent with the primary analysis. The NMA suggested lower CIN2+ occurrence for all vaccine-type categories compared with no vaccination; however, all comparisons were indirect through a common no-vaccination comparator, so vaccine-type differences should be interpreted as exploratory.

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.