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

Socioeconomic Status Is Associated With Antibody Levels Against Vaccine Preventable Diseases in the Netherlands.

Background: We investigated whether low socioeconomic status (SES), which is associated with reduced health and life expectancy, might play a role in increased risk for infectious diseases. Therefore, we explored the association between SES and immunoglobulin G (IgG) levels against various pathogens. Methods: We analyzed the association between SES [educational level and net household income (NHI)] and serum IgG concentration against measles, mumps, rubella, varicella, Haemophilus influenzae type B (HiB), pneumococcus, meningococcus serogroup C (MenC), and cytomegalovirus (CMV) collected within a national cross-sectional serosurvey (2006/2007) using linear regression analyses among non-vaccinated individuals. Results: Higher educational level was associated with higher IgG concentrations against measles (GMC ratio 1.34, 95% CI 1.18-1.53) and rubella (1.13, 1.02-1.25) compared to low education level. In contrast, higher education level was associated with lower IgG concentrations against pneumococcus (0.78, 0.70-0.88), MenC (0.54, 0.44-0.68), and CMV (0.23, 0.18-0.31) compared to low education level. This pattern was also evident when NHI was used as SES indicator. Conclusion: Our study suggests that socioeconomic status is associated with antibody levels in a pathogen-dependent manner. The results suggest that differences in serological response upon infection or differences in exposure might be involved in the variation in IgG levels between SES groups

Changes in HPV Seroprevalence from an Unvaccinated Toward a Girls-Only Vaccinated Population in the Netherlands.

Serum samples of men and women were used from two cross-sectional population-based serosurveillance studies performed before (2006-07, n = 6,384) and after (2016-17, n = 5,645) implementation of HPV vaccination in the Netherlands. Seven high-risk HPV-specific antibodies (HPV16, 18, 31, 33, 45, 52, and 58) were tested in a virus-like particle-based multiplex immunoassay

Changes in HPV Seroprevalence from an Unvaccinated Toward a Girls-Only Vaccinated Population in the Netherlands.

Serum samples of men and women were used from two cross-sectional population-based serosurveillance studies performed before (2006-07, n = 6,384) and after (2016-17, n = 5,645) implementation of HPV vaccination in the Netherlands. Seven high-risk HPV-specific antibodies (HPV16, 18, 31, 33, 45, 52, and 58) were tested in a virus-like particle-based multiplex immunoassay

Vaccine Effectiveness Following Routine Immunization With Bivalent Human Papillomavirus (HPV) Vaccine: Protection Against Incident Genital HPV Infections From a Reduced-Dosing Schedule

BACKGROUND: In the Netherlands, the bivalent human papillomavirus (HPV) vaccine has been offered to preadolescent girls via the National Immunization Program in a 2-dose schedule since 2014. The current study estimates vaccine effectiveness (VE) against HPV infections up to 4 years postvaccination among girls eligible for routine 2-dose immunization. METHODS: A cohort study (HAVANA2) was used in which participants annually filled out an online questionnaire and provided a vaginal self-sample for determination of HPV by the SPF10-LiPA25 assay, able to detect 25 HPV types. VE against incident type-specific infections and pooled outcomes was estimated by a Cox proportional hazards model with shared frailty between the HPV types. RESULTS: In total, 2027 girls were included in the study, 1098 (54.2%) of whom were vaccinated with 2 doses. Highest incidence rate was 5.0/1000 person-years (HPV-51) among vaccinated participants and 9.1/1000 person-years (HPV-74) among unvaccinated participants. Adjusted pooled VE was 84.0% (95% confidence interval [CI], 27.0%-96.5%) against incident HPV-16/18 infections and 86.5% (95% CI, 39.5%-97.08%) against cross-protective types HPV-31/33/45. CONCLUSIONS: Four years postvaccination, 2 doses of bivalent HPV vaccine were effective in the prevention of incident HPV-16/18 infections and provided cross-protection to HPV-31/33/45. Our VE estimates rival those from 3-dose schedules, indicating comparable protection by 2-dose schedules

Vaccine effectiveness following routine immunization with bivalent HPV vaccine: Protection against incident genital HPV infections from a reduced-dosing schedule.

BACKGROUND: In the Netherlands, the bivalent human papillomavirus (HPV) vaccine has been offered to preadolescent girls via the National Immunization Program in a 2-dose schedule since 2014. The current study estimates vaccine effectiveness (VE) against HPV infections up to 4 years postvaccination among girls eligible for routine 2-dose immunization. METHODS: A cohort study (HAVANA2) was used in which participants annually filled out an online questionnaire and provided a vaginal self-sample for determination of HPV by the SPF10-LiPA25 assay, able to detect 25 HPV types. VE against incident type-specific infections and pooled outcomes was estimated by a Cox proportional hazards model with shared frailty between the HPV types. RESULTS: In total, 2027 girls were included in the study, 1098 (54.2%) of whom were vaccinated with 2 doses. Highest incidence rate was 5.0/1000 person-years (HPV-51) among vaccinated participants and 9.1/1000 person-years (HPV-74) among unvaccinated participants. Adjusted pooled VE was 84.0% (95% confidence interval [CI], 27.0%–96.5%) against incident HPV-16/18 infections and 86.5% (95% CI, 39.5%–97.08%) against cross-protective types HPV-31/33/45. CONCLUSIONS: Four years postvaccination, 2 doses of bivalent HPV vaccine were effective in the prevention of incident HPV-16/18 infections and provided cross-protection to HPV-31/33/45. Our VE estimates rival those from 3-dose schedules, indicating comparable protection by 2-dose schedules