Vaccination protects against invasive HPV‐associated cancers
Human papillomavirus (HPV) vaccines were already in clinical trials highly efficacious against infection and cervical intraepithelial neoplasia grade 3 (CIN3).1-3 Population-based cancer-registry follow-up of two Finnish vaccination trial cohorts and unvaccinated control cohorts has proved their sustained protective effectiveness against CIN3 irrespectively of HPV type 10 years post vaccination4, 5 but efficacy against invasive cancer has remained open. We report findings made in conjunction of the cancer-registry follow-up's interim analysis5 now using invasive cancer as the end-point for all our different, originally 14- to 19-year-old HPV vaccinated and unvaccinated female cohorts. The first two cohorts were recruited in 2002–2005 to FUTURE II (NCT00092534)4 (HPV 6/11/16/18-vaccine) phase III trial and PATRICIA (NCT00122681)5 (HPV 16/18 vaccine) phase III trial, continued in Finland as a passive long-term follow-up study (NCT01393470).5 Participants of the FUTURE II4 and PATRICIA5 trial cohorts comprised 866 and 2,465 HPV6/11/16/18 and HPV16/18 vaccinated, originally 16- to 17-year-old Finnish women. Concomitantly 15,665 unvaccinated 18- to 19-year-old women from adjacent birth cohorts, not eligible to the clinical phase III trials, were enrolled to a passive comparison cohort.2, 3 In addition, in 2007–2008, 6,198 HPV16/18 vaccinated and 2,173 hepatitis B-virus vaccinated 14- to 15-year-old women (not cross-vaccinated against HPV16/18) were enrolled in 2007–2008 to a community-randomized phase IV trial (NCT00534638) on the impact of gender-neutral vs. girls-only vaccination strategies.6 Age-aligned,4, 5 country-wide Finnish Cancer Registry-based follow-up of all the above-mentioned cluster and/or individually randomized cohorts for comparable up to 7-year time-periods between June 2007 and December 2015 resulted in 65,656 and 124,245 follow-up years for HPV-vaccinated and non-HPV vaccinated women. Thus, also the 866 + 2,465 originally 16- to 17-year-old HPV vaccinated and the 15,665 18- to 19-year-old unvaccinated women were of the same age during the follow-up. We found 10 cases with invasive carcinomas a priori established as cancers caused by HPV7 (eight cervical cancers, one oropharyngeal cancer and one vulvar cancer) in non-HPV vaccinated women but no cases in HPV vaccinated women (Table 1). The overall vaccine efficacy (VE) estimate8 100% is statistically significant albeit with somewhat wide confidence interval (95% CI 16, 100) apparently due to the small end-point frequencies. Incidence rates of other, non-HPV associated common cancers did not differ between the non-vaccinated and HPV vaccinated women (Table 1). This is the first intention-to-treat trial evidence that vaccination protects against invasive HPV-associated cancer, an awaited, pivotal corollary to the high VE against HPV infection3 and the established carcinogenicity of the infection.7 The passive cancer-registry follow-up of our intervention and non-intervention cohorts continues, with a possibility to retrieve diagnostic histopathological blocks for HPV typing.5 The per protocol analysis in 2019 is powered to provide HPV type-specific vaccine efficacy estimates against HPV-associated cancers.