Evidence from Outcomes: Gender-Neutral 2vHPV Vaccination at Moderate Coverage Drives Rapid Depletion of HPV16/18 Among Vaccinated and Unvaccinated Women

Human papillomavirus (HPV) vaccination may eventually eradicate oncogenic vaccine-targeted HPVs but only with a strategy that also protects unvaccinated individuals. We compared the impact of gender-neutral and girls-only vaccination strategies on the indirect and direct protection of unvaccinated and vaccinated young women against HPV16/18 infection using HPV16/18 seropositivity and PCR positivity 3-7 years post vaccination as the outcome measure. A total of 33 Finnish communities were randomized to one of three vaccination strategies: bivalent gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or control hepatitis B vaccination (Arm C). All individuals born between 1992 and 1995 and residing in these communities (n = 80,272) were invited to participate. Overall, 11,662 males and 20,513 females consented, corresponding to vaccination coverages of 25% and 45%, respectively, in 2007-2009. Between 2010 and 2014, 11,396 cervical samples were collected from 18-year-old participants and subjected to high-throughput PCR-based HPV genotyping. In addition, serum samples were obtained from 8022 unvaccinated women under 23 years of age residing in Arm A (n = 2657), Arm B (n = 2691), or Arm C (n = 2674) communities during the pre-vaccination (2005-2010) and post-vaccination (2011-2016) periods. To assess indirect vaccine effects using PCR and serological outcomes in unvaccinated women, we compared reductions in HPV16/18 prevalence from baseline within the gender-neutral and girls-only vaccination arms, using the control arm as a reference. A significant decrease in seroprevalence between the pre- and post-vaccination periods was detected in the gender-neutral communities for both HPV16 (seroprevalence ratio = 0.64) and HPV18 (0.72), whereas no comparable reductions were observed in the girls-only or control communities. In contrast, a significant reduction in HPV18 PCR-based prevalence from baseline to the post-vaccination period was observed in both the gender-neutral (0.32) and girls-only (0.61) communities. However, after accounting for ratios of seroprevalence rations for secular trends, the corresponding decrease in HPV18 seroprevalence was no longer statistically significant. Vaccine efficacy (VE) in Arm A or Arm B versus Arm C of vaccinated women measured the direct protection of vaccinated women by vaccination strategy. HPV16/18 VEs varied between 89% and 96% with some indication of herd effect against HPV18. Robust effectiveness of vaccination against PCR-confirmed cervical HPV16/18 infections, along with rapid indirect protection against HPV16/18 and HPV18 infections, was evident even with vaccination reaching only 25% and 45% coverage. Our results suggest that vaccine efficacy and herd effect induced by gender-neutral 2vHPV vaccination sets the stage for comprehensive HPV eradication, including the unvaccinated in the vaccinated communities.