HPV16/18 vaccination in the Netherlands: Monitoring long-term effects on HPV infections and immunogenicity

Human papillomavirus is one of the most common sexually transmittable infections. An infection with a hr HPV type can persist and cause the development of malignancies on the anogenital site and in the head and neck region. To strongly reduce the transmission of HPV and development of (cervical) cancer, prophylactic, bivalent HPV vaccination was introduced into the Dutch NIP in 2009 as a girls-only vaccine, preventing the most oncogenic HPV types 16 and 18. The current thesis describes monitoring of the routine HPV vaccination program within the Netherlands using intermediate endpoints, given the large gap between occurrence of HPV infection and development of cancer. Serological measurements are important in vaccination research and evaluation, since they can provide information on the responsiveness to a vaccine. Therefore, in chapter 2, the populationbased changes in seroprevalence of unvaccinated individuals were evaluated over a ten-year time period, during which HPV vaccination was implemented in the Netherlands. IgG antibody levels to seven hr HPV types as induced by natural infection showed that seroprevalence increased over the past decade among unvaccinated women, while it was stable among men. A lower seroprevalence among young women or herd effects among men, which may follow from the recent introduction of the HPV vaccination program among teenage girls in the Netherlands, was not yet observed. In chapter 3, the focus was on vaccine derived immune responses. Antibody levels remained high up till nine years past vaccination (three doses), both for vaccine types and to some extent for cross protective types. Immune responses from vaccinated women who presented with an HPV infection were compared to immune responses from women without infection, but the difference was not significant in the year before infection. This indicates that an immune correlate of protection, i.e. a threshold that should be reached in order to be protected, cannot be easily determined. This was also described in chapter 4, where we provided a review of the currently available information about immunological responses following vaccination with three different HPV vaccines, with special attention to long-term effects and dosing schedules. In chapter 5 we used data from sexual health clinic visitors (Passyon study) to assess trends of type-specific HPV prevalence over time since the introduction of HPV vaccination. Both among vaccinated women, heterosexual men, and unvaccinated women, declining trends of vaccine HPV types 16 and 18 were observed. This indicates that the population-level impact of a girls-only HPV vaccination program extends beyond the targeted group, inducing first- and secondorder herd effects. Chapter 6 focused on the vaccine effectiveness of two doses of routinely provided HPV vaccination. Genital infections among vaccinated (two doses) and unvaccinated participants from the HAVANA2 cohort were compared and indicated high, significant vaccine effectiveness against vaccine type infections (HPV16/18) and cross protective type infections (HPV31/33/45) up to four years after vaccination. In chapter 7, methodological challenges regarding vaccine effectiveness estimates were described, specifically the selection of the right method. Different statistical methods as identified in the literature were described, compared, and applied to the HAVANA data in order to identify the most robust method for VE estimates from observational cohort data. Although deviations in the calculated VE against persistent HPV16/18/31/33/45 infections were limited, the PWP-TT approach was selected as preferable for the current data. The method of choice was applied in chapter 8, where we studied the long-term protection from the three-dose schedule up to 10 years after vaccination using HAVANA data. No indication of waning protecting over time was observed, as the VE against persistent vaccine type infections remained very high. This was also the case for cross protective HPV types.