Reduction in HPV16 and HPV18 Prevalence Among Young Women with Low- and High-Grade Cervical Lesions Following the Japanese HPV Vaccination Program: 6-Year Analysis of the MINT Study

Background The Japanese government began the national human papillomavirus (HPV) vaccination program for girls aged 12-16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. Methods To evaluate the population-level impact of HPV vaccination implemented for only 3 years in Japan, women aged <40 years newly diagnosed with cervical intraepithelial neoplasia grade 1-3 (CIN1-3), adenocarcinoma in situ (AIS) or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. Findings A total 7709 women were registered during 2012-2017, of which 5045 were HPV-genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6-year period were observed in CIN1 (50.0% to 0.0%, Ptrend<0.0001) and CIN2-3/AIS (83.3% to 45.0%, Ptrend=0.07) among women aged <25 years; no similar decline was observed for older age groups. Overall, HPV vaccination reduced the proportion of HPV16/18-attributable CIN2-3/AIS from 47.7% to 33.0% (P=0.003): from 43.5% to 12.5% as the national vaccination (P=0.08) and from 47.8% to 36.7% as catch-up vaccination (P=0.04). HPV16/18 prevalence in CIN2-3/AIS cases was significantly reduced among females that received first vaccination at age ≤20 years (P=0.02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged <25 years. Interpretation We found HPV vaccination to be effective in protecting against HPV16/18-positive CIN/AIS in Japan; however, our data did not support catch-up vaccination for women aged >20 years. Older adolescents who skipped routine HPV vaccination owing to the Japanese government's suspension of recommendation may benefit from receiving catch-up HPV vaccination before they reach age 20 years. Clinical Trial Registration: This study was registered in the UMIN Clinical Trials Registry as UMI08891. Funding Statement: The Foundation for Advancement of International Science (FAIS) and the Japanese Agency of Medical Research and Development (AMED) (grant number: 19fk0108098). Declaration of Interests: Koji Matsumoto received lecture fees from HOLOGIC Japan, Inc. and MSD K.K., and research grants from MSD K.K. Kimio Ushijima received lecture fees from MSD K.K. Ethical Approval Statement: Institutional ethical and research review boards of the participating institutions have approved the study protocol.