Moderate Coverage Vaccination Eradicates Oncogenic Human Papillomaviruses if a Gender-Neutral Strategy is Applied

Background: Very high coverage human papillomavirus (HPV) vaccination of girls has the potential to eradicate some HPV types but low coverage vaccination does not. The protection of unvaccinated individuals by herd effect (HE) varies by HPV type and vaccination strategy. By combining community-randomized trial data and mathematical modeling we show that gender-neutral vaccination is superior for achieving eradication of oncogenic HPVs. Methods: We randomized 33 communities into gender-neutral HPV16/18 vaccination (A), HPV16/18 vaccination of girls only (B), and hepatitis B-virus vaccination of boys and girls (C). From 2007-2010 11,622/40,852 resident boys and 20,513/39,420 resident girls born 1992-1995 consented to the study. At follow-up in 2010-14, cervicovaginal samples from vaccinated and unvaccinated girls were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68. Trial-based vaccine efficacy (VE) and HE, estimated among non-HPV vaccinated arm A/B girls using arm C controls, were weighted for mean protective effectiveness (PE) estimation, and used for modeling eradication.   Findings The HPV18/31/33 HE and PE were significant in younger birth cohorts: four years post vaccination HE and PE were 150% and 40% stronger in the gender-neutral than in the girls-only arm. HPV18/31/33 have moderate to fast clearance rates enabling eradication, and corresponding HEs from vaccinated to unvaccinated arose rapidly. HPV18/31/33 eradication in adolescents/young adults is predicted in 20 years with 75% coverage of gender-neutral vaccination, eradication of HPV16 is predicted within 30 years.   Interpretation While low coverage with a girls-only vaccination strategy leaves most females unprotected, HPV-disease eradication of oncogenic HPVs is certain with moderate coverage gender-neutral vaccination strategy.   Funding: This ancillary study was partially funded by Academy of Finland, Finnish Cancer Organizations and EU FP7 networks PREHDICT and CoheaHR. GlaxoSmithKline Biologicals SA funded the primary study HPV-040 (NCT00534638, data to be published in a separate manuscript) but was not involved in the conduct of this ancillary study. GlaxoSmithKline Biologicals SA was provided the opportunity to review this manuscript for accuracy of primary HPV-040 data but the authors are solely responsible for final content and interpretation. V.N.P. was supported by a personal grant from the Ministry of Health, Government of Catalonia (PERIS SLT002/16/00496). Declaration of Interest: D.A., J.D., G.G., M.L. and J.P. have received grants from Merck & Co. Inc. or the GSK group of companies through their employers [Family Federation Finland (DA), Karolinska Institute (J.D., M.L.), Universities of Tampere (M.L.) or Helsinki (J.P.) or Imperial College London (G.G.)] for HPV vaccination studies. G.D. is currently a full time employee of Takeda Vaccines, but was working for GSK Biologicals at the time the study was planned and conducted. He holds several patents in the HPV field which have been assigned to the GSK groups of companies and has stock shares in both the GSK groups of companies and Takeda. Ethical Approval: The HPV-040 study (Eudra-CT-2007-001731-55, NCT00534638), and parallel ancillary studies on Chlamydia trachomatis screening (Dnro 111/2009) and HPV screening (ETL-code 13149, NCT02149030) were approved by Finnish ethical committees of the Pirkanmaa and PohjoisPohjanmaa hospital districts in 2007, 2009 and 2013, respectively.