Quadrivalent Human Papillomavirus Vaccine and High-Grade Vulvovaginal Lesions.

Importance: Human papillomavirus (HPV) vaccination has been associated with reduced risk of high-grade cervical lesions. However, evidence on its association with high-grade vulvovaginal lesions remains scarce. Objective: To evaluate the association between quadrivalent HPV vaccination and high-grade vulvovaginal lesions and assess the population-level incidence reduction among birth cohorts eligible for various vaccination programs. Design, Setting, and Participants: This population-based cohort study included women who were born between 1985 and 1998 and resided in Sweden between 2006 and 2022. Eligible participants had not previously received an HPV vaccination and did not have high-grade vulvovaginal lesions. Data were analyzed from February to October 2025. Exposure: HPV vaccination status was treated as a time-varying exposure, and birth cohorts corresponded to different vaccination programs: 1985 to 1988 (opportunistic vaccination program), 1989 to 1992 (subsidized vaccination), and 1993 to 1998 (catch-up vaccination). Main Outcome and Measures: The main outcome was incidence of high-grade vulvovaginal lesions, including cancers. Poisson regression models were used to estimate incidence rate ratios with 95% CIs. Results: Among 778 943 women, a total of 256 353 (32.9%) received at least 1 dose of the quadrivalent HPV vaccine. The median (IQR) follow-up duration was 17.0 (17.0-17.0) years for unvaccinated women, 12.2 (10.6-13.4) years for those vaccinated between ages 10 and 16 years, and 10.8 (9.3-13.5) years for those vaccinated at 17 years or older. During follow-up, 98 cases of high-grade vulvovaginal lesions were found in vaccinated women, and 547 cases were found in unvaccinated women. Compared with unvaccinated women, the fully adjusted incidence rate ratio of high-grade vulvovaginal lesions was 0.63 (95% CI, 0.50-0.81) in vaccinated women. Stratified by age at vaccination, the incidence rate ratios for those vaccinated at 10 to 16 years and 17 years or older were 0.45 (95% CI, 0.32-0.65) and 0.80 (95% CI, 0.61-1.06), respectively. Compared with women born between 1985 and 1988, the incidence rate ratios for those born in 1989 to 1992 and 1993 to 1998 were 0.81 (95% CI, 0.67-0.97) and 0.62 (95% CI, 0.49-0.80), respectively. Conclusions and Relevance: In this cohort study, vaccinated women had a lower incidence of high-grade vulvovaginal lesions compared with unvaccinated women, with a greater incidence reduction for those vaccinated at younger ages (before 17 years of age). Population-level incidence reduction was observed in cohorts vaccinated through subsidized or catch-up programs. These findings support that scaling up coverage of HPV vaccination at younger ages may help prevent high-grade vulvovaginal lesions.