Population-Based Human Papillomavirus Serosurvey Reveals HPV16/18 Herd Effect But No Clear Type-Replacement in Unvaccinated Females 6 Years Post Gender-Neutral Vaccination in a Cluster Randomised Trial

Abstract

Background: Human papillomavirus (HPV) basic reproductive numbers are low, except for HPV type 16. Thus, vaccination can induce herd effects to reduce the prevalence of many HPV types, especially if gender-neutral vaccination strategy and a vaccine with broad protection against HPV types are used. Methods: We used a cluster-randomized trial implemented in 2007-2009 among early, 1992-1995 born adolescents to create differential herd effects in 11 communities with gender-neutral (Arm A), and 11 communities with girls-only (Arm B) HPV16/18 vaccination achieving 20% coverage in Arm A boys and 45% coverage in Arm A and Arm B girls. In 11 control communities, devoid of any opportunistic HPV vaccination, hepatitis B-virus vaccination covered 30% of boys and 50% of girls. Seroprevalence was assessed for 17 HPV types in consecutive calendar-time (2005-07, 2008-10, 2011-13, 2014-16) strata comprising unvaccinated adolescent and young adult females, who were respectively 19 years or younger, and 20 to 22 years of age at the time of serum sampling. Sexual risk-taking behaviour core-group was defined by herpes simplex virus type-2 antibody positivity. From observed data probabilistic networks and simulated equal size seroprevalence datasets (N=100,000) were also derived. Findings: Following gender-neutral vaccination significant HPV16/18 herd effects were rapidly detected in the adolescent core-group of the gender-neutral vaccination Arm A. HPV51 prevalence tended to increase later in the post-vaccination era (2014-16) among adolescent core-group girls-only vaccination Arm B, as also supported by the simulations. Interpretation: Low to moderate coverage HPV vaccination induces a strong herd effect against HPV16/18 infection reducing circulation of vaccine-targeted HPV types following gender-neutral vaccination. The ecological niche vacated is not immediately filled. Funding Statement: This study was partially funded by Academy of Finland, Finnish Cancer Organizations and EU FP7 networks PREHDICT and CoheaHR. GlaxoSmithKline Biologicals SA funded the community randomized HPV-040 trial (NCT00534638), (data to be published in a separate manuscript) however was not in any way involved in the conduct of this study. This study received some support via a personal grant from the Ministry of Health, Government of Catalonia (PERIS SLT002/16/00496).The study was supported by grants from the Swedish Cancer Society (CAN 2015/399 and CAN 2017/459), from the Swedish Foundation for Strategic Research (grant number RB13-0011) and from Karolinska Institutet (Dnr. 2018-01523). ML received funding from KI to his Professorship (Dnr. 2-3698/2017). Declaration of Interests: JD and ML have received grants from Merck & Co. Inc and the GSK group of companies through their employers the Karolinska Institute (both JD and ML), or the University of Tampere (ML) for conducting HPV vaccination studies. Ethics Approval Statement: The community randomized study obtained permissions from the Ethical Review Board of Pirkanmaa Hospital District (R07113M 14.6.2007) and the Ethical Review Board of North Bothnia Hospital District (EETTMK:111/2009). Informed consent to use the FMC serum samples for research purposes is granted by the pregnant women when they donate their 1st trimester sample for screening of congenital infections.