The indirect effect of the bivalent human papillomavirus vaccination program: an observational cohort study

The impact of human papillomavirus (HPV) vaccination programs depends on the degree of indirect protection against new infections achieved among unvaccinated women. We estimated the indirect effect of bivalent HPV vaccination by comparing the HPV-type incidence in unvaccinated female participants between a cohort offered vaccination in 2009/2010 and a cohort of similar-aged women offered vaccination in 2014.

We compared the incidence rates of HPV types in the HAVANA cohort (follow-up from 2010/2011 until 2015/2016) with those from the HAVANA-2 cohort (2017-2022) using two regression approaches to estimate the indirect effect of HPV vaccination. First, we calculated the incidence ratio (IRR) for a vaccine or cross-protective type in HAVANA-2 versus HAVANA by Poisson regression and compared it to the IRR for a non-cross-protective type. The indirect vaccine effect is defined as 1-ratio of the IRRs. Second, we performed Cox regression with infection by vaccine or cross-protective type as the endpoint and calculated the hazard ratio (HR) for HAVANA-2 versus HAVANA after adjusting for time-varying sociodemographic variables. The indirect effect is defined as 1-HR.

We included 661 unvaccinated participants in HAVANA and 927 in HAVANA-2. We observed a significant reduction in incident HPV16 infections of 70.9% (95% CI 48.3-83.7%) with Poisson regression and of 73.1% (95% CI 53.3-84.5%) with Cox regression. For HPV45, significant decreases of 67.3% (95% CI 8.8-88.3%) and 69.8% (95% CI 15.2-89.3%) were observed. For HPV18, HPV31, and HPV33, the indirect effect was not statistically significant.

Large indirect effects of the bivalent HPV vaccination program were observed for HPV16 and HPV45 infections.