Cost-effectiveness of female-only and gender-neutral HPV vaccination strategies in Japan

This study evaluated the cost-effectiveness of female-only vaccination (FOV) and gender-neutral vaccination strategies (GNV) using 4-valent (4vHPV) and 9-valent HPV (9vHPV) vaccines among adolescents aged 12–16 years in Japan. It provides the first comprehensive assessment of all feasible vaccine–population combinations using a unified dynamic transmission model. An age- and sex-structured dynamic transmission model simulated HPV transmission and disease progression over 100 years, incorporating cervical, vulvar, vaginal, anal, head and neck, and penile cancers. Six vaccination strategies were evaluated: no further vaccination, FOV with 4vHPV, FOV with 9vHPV, GNV with 9vHPV for females and 4vHPV for males, GNV with 4vHPV for both sexes, and GNV with 9vHPV for both sexes. Analyses adopted a healthcare payer perspective, with costs in 2025 Japanese yen, discounted at 3%. Incremental cost-effectiveness ratios (ICERs) were calculated using a willingness-to-pay threshold of ¥5 million per quality-adjusted life year (QALY). FOV with 4vHPV yielded an ICER of ¥171,725/QALY versus no vaccination, and FOV with 9vHPV yielded ¥1,366,226/QALY versus FOV with 4vHPV – both below the willingness-to-pay threshold. Furthermore, GNV with 9vHPV for both sexes provided the greatest health gains and remained below the threshold (¥3,594,296/QALY) versus FOV with 9vHPV. GNV with 4vHPV and mixed 9vHPV/4vHPV schedules were dominated and excluded. The healthcare payer perspective excludes indirect costs. The model hypothetically includes 9vHPV for boys despite its unavailability for males in Japan. Both female-only 4vHPV and 9vHPV strategies are cost-effective under Japan’s economic standards. Furthermore, GNV with 9vHPV provides greater health benefits and cost-effectiveness. Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and a major cause of cervical, vulvar, vaginal, anal, head and neck, and penile cancers. In Japan, HPV vaccination coverage dropped sharply after the government suspended its recommendation in 2013 due to safety concerns, although it was reinstated in 2021. The 9-valent HPV vaccine was added to Japan’s National Immunization Program in 2023. Currently, girls aged 12–16 years can receive either vaccine free of charge, whereas boys must pay out-of-pocket, limiting access and creating gender inequality in protection. This study evaluated the cost-effectiveness of female-only and gender-neutral vaccination strategies using both vaccines among adolescents aged 12–16 years. Using a dynamic transmission model over a 100-year time horizon, we compared six strategies incorporating multiple HPV-related diseases. Two strategies were (weakly) dominated and excluded: gender-neutral 4-valent vaccination for both sexes, and 9-valent for girls with 4-valent for boys. Among the remaining strategies, female-only 4-valent vaccination showed an incremental cost-effectiveness ratio (ICER) of approximately ¥171,725 per quality-adjusted life year (QALY) compared with no further vaccination. Upgrading to 9-valent vaccine yielded an ICER of ¥1.4 million per QALY. Gender-neutral 9-valent vaccination for both sexes showed an ICER of ¥3.6 million per QALY, providing the largest health gains. All strategies remained below Japan’s willingness-to-pay threshold of ¥5 million per QALY. Sensitivity analyses at 70% coverage confirmed robustness. This study demonstrates that gender-neutral 9-valent vaccination achieves the greatest health impact while remaining cost-effective.