HPV16/18 vaccination in the Netherlands: Monitoring long-term effects on HPV infections and immunogenicity
Authors:   , Hoes Joske 
Published: September 2023

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.