Association Between Human Papillomavirus Vaccination and the Risk of Cervical Cancer and Precancerous Lesions in Israel: A Retrospective Cohort Study

Background: Human papillomavirus (HPV) infection is the necessary cause of almost all cervical cancers. HPV vaccination programs have been implemented worldwide, yet real-world evidence on vaccine effectiveness against invasive cervical cancer remains limited. Methods: We conducted a retrospective cohort study using synthetically generated data from a large health provider in Israel, including women who underwent a first Papanicolaou (Pap) test during 2014-2015. Their HPV-vaccination status before an index Pap test was obtained from computerized records. Incident cervical cancer and high-grade cervical pathology (cervical cancer, cervical intraepithelial neoplasia CIN 1-3, and carcinoma in situ) occurrence were examined through 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and fitted with propensity score weighting. Results: The cohort included 98,102 women, of whom 9198 (9.4%) were vaccinated against HPV before an index Pap test. While HPV-vaccinated women had a higher risk of cervical pathology compared with unvaccinated women, among women vaccinated before age 18, HPV vaccination was associated with a substantially lower, though not statistically significant, risk of cervical cancer (HR 0.28, 95% CI: 0.07-1.20, p = 0.087). Conclusions: In this large cohort, HPV vaccination was correlated with a higher risk of cervical pathology, likely reflecting residual confounding factors from sexual behavior and differential baseline risks of HPV infection. In contrast, vaccination during adolescence showed a marked trend toward a reduced risk of cervical cancer, consistent with international evidence that early vaccination, prior to HPV exposure, is the most effective preventative treatment.