Effect of Human Papillomavirus (HPV) Vaccine on Male Genital Disease: A Meta-Analysis of Randomised Controlled Trials

Human papillomavirus (HPV) is a major cause of genital diseases and cancers in both sexes, including cervical, penile, anal, and oropharyngeal cancers, as well as genital warts. Although HPV vaccination programs initially targeted females due to their link with cervical cancer, increasing recognition of HPV-related disease burden in males has led to advocacy for gender-neutral vaccination. This meta-analysis assessed the effectiveness of HPV vaccination in preventing genital diseases among males by synthesising data from randomised controlled trials (RCTs). A systematic PubMed search was conducted in July 2025 following PRISMA guidelines. Studies involving HPV-vaccinated males compared with placebo recipients were included, and data were extracted independently by two different reviewers. The Joanna Briggs Institute checklist was used to assess the study quality. The random-effects model in Review Manager 5.4 (The Cochrane Collaboration, Copenhagen, Denmark) was used to calculate pooled risk ratios with their 95% confidence intervals (CIs). Out of 120 screened studies, four RCTs met the inclusion criteria, comprising 4,200 male participants (2,091 vaccinated and 2,109 controls). The pooled analysis yielded a relative difference (RD) of -0.03 (95% CI: -0.04 to -0.01), indicating a statistically significant difference in the risk of genital disease between vaccinated and unvaccinated males. Two trials showed statistically non-significant protective effects, while two did not, suggesting that differences in study design and baseline HPV exposure influenced the outcomes. Despite the lack of statistical significance, the direction of effect aligns with previous evidence of strong vaccine-induced protection in HPV-naïve males, with reported efficacy exceeding 90% against genital warts and anal intraepithelial neoplasia (AIN). These findings emphasise the benefit of early vaccination before sexual initiation, though partial protection may also occur in previously exposed or high-risk populations, such as men who have sex with men (MSM) and people living with HIV/AIDS (PLWHA). Although global HPV vaccine coverage in males remains low, cost-effectiveness analyses justify expanding vaccination programs when accounting for male disease burden and community-level benefits. In conclusion, this meta-analysis suggests that HPV vaccination may lower the risk of genital diseases in males by approximately 3%, supporting its role in comprehensive HPV prevention. Broader implementation of early and gender-neutral vaccination, along with targeted strategies for high-risk groups, is essential for equitable control of HPV-related morbidity and mortality worldwide.