Highlights
The 9-valent HPV vaccine demonstrates significant protective efficacy against HPV-related malignancies in adolescent and young adult males. Key findings from this large-scale investigation include:
* Vaccinated males exhibited a 46% lower risk of developing HPV-related cancers compared to unvaccinated individuals, with a hazard ratio of 0.54 (95% CI, 0.37-0.81; P=0.002).
* Subgroup analysis confirmed vaccine efficacy across age cohorts—males aged 9-14 years showed a 42% risk reduction, while those aged 15-26 years achieved a 50% reduction.
* The study, utilizing a global database spanning January 2016 to December 2024 with up to 10 years of follow-up, represents one of the most comprehensive evaluations of 9-valent HPV vaccine effectiveness in males to date.
Background: The Unmet Burden of HPV-Related Cancers in Males
Human papillomavirus (HPV) infections remain a significant global health concern, responsible for approximately 5% of all cancers worldwide. While HPV-associated malignancies have traditionally been framed as a female health issue—particularly cervical cancer—the disease burden in males is substantial and increasingly recognized in clinical practice.
HPV-related cancers affecting males encompass several anatomical sites: oropharyngeal squamous cell carcinomas (head and neck region), esophageal cancer, anal cancer, and penile cancer. These malignancies collectively contribute to considerable morbidity, mortality, and healthcare expenditures. Despite the availability of highly effective HPV vaccines since the mid-2000s, vaccination coverage among males has historically lagged behind female rates in many regions, partly due to earlier recommendations that prioritized female immunization for cervical cancer prevention.
The introduction of the 9-valent HPV vaccine (Gardasil 9), which provides protection against nine HPV genotypes including those most commonly associated with anogenital and oropharyngeal cancers, has expanded the potential for population-level protection. However, robust evidence specifically demonstrating vaccine effectiveness in males has remained limited, creating uncertainty among healthcare providers and policymakers regarding the implementation of sex-neutral vaccination strategies.
This study addresses that evidence gap by evaluating the incidence of HPV-related cancers between vaccinated and unvaccinated males using a large-scale global database, providing critical data to inform clinical practice and public health policy.
Study Design
This multicenter retrospective cohort study leveraged a comprehensive global database to investigate the association between 9-valent HPV vaccination and HPV-related cancer incidence in males. The study population comprised males aged 9 to 26 years who either received at least one dose of the 9-valent HPV vaccine or remained unvaccinated during the study period.
Participants were enrolled between January 2016 and December 2024, with outcomes followed for up to 10 years. This extended follow-up period allows for meaningful assessment of vaccine effectiveness against cancers that may develop over prolonged latency periods following HPV infection.
The primary composite outcome included HPV-related cancers across four anatomical sites: head and neck cancer (predominantly oropharyngeal), esophageal cancer, anal cancer, and penile cancer. To minimize confounding inherent in observational research, investigators employed propensity score matching—a statistical technique that creates comparable groups based on measured covariates such as age, geographic region, and healthcare access indicators.
Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to quantify the association between vaccination status and cancer incidence. Statistical significance was set at P<0.05.
Results
Study Population and Baseline Characteristics
Prior to propensity score matching, the study identified 615,155 vaccinated males with a mean age of 13.4 years (SD 3.5) and 2,290,623 unvaccinated males with a mean age of 17.2 years (SD 5.5). Following propensity score matching, 510,260 participants were included in each group, creating well-balanced cohorts for comparative analysis.
Primary Outcome: Composite HPV-Related Cancer Incidence
The vaccinated group demonstrated a significantly lower risk of the primary composite outcome compared to unvaccinated males. The hazard ratio of 0.54 (95% CI, 0.37-0.81) indicates a 46% reduction in HPV-related cancer risk among vaccinated individuals, with this association achieving statistical significance (P=0.002).
This finding suggests that 9-valent HPV vaccination provides meaningful protection against HPV-related malignancies in males, extending the documented benefits of vaccination beyond female populations.
Subgroup Analysis by Age
Stratified analysis by age cohort revealed consistent protective effects across developmental stages:
* Males aged 9-14 years: The vaccinated group demonstrated a hazard ratio of 0.58 (95% CI, 0.34-0.97; P=0.04), representing a 42% risk reduction. This finding supports early vaccination during adolescence, aligning with current recommendations for routine immunization at ages 11-12 years.
* Males aged 15-26 years: A hazard ratio of 0.50 (95% CI, 0.27-0.93; P=0.03) was observed, indicating a 50% risk reduction. This result demonstrates that catch-up vaccination in older adolescents and young adults remains beneficial.
Both age subgroups maintained statistically significant reductions in HPV-related cancer incidence, suggesting that vaccination programs can achieve meaningful protection across a wide age range.
Clinical and Public Health Implications
The magnitude of risk reduction observed in this study is consistent with vaccine efficacy data from randomized controlled trials and post-licensure surveillance studies in female populations. The 9-valent vaccine targets HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, which collectively account for the majority of HPV-related malignancies across anatomical sites.
Importantly, the protective effect persisted even in the older age subgroup (15-26 years), suggesting that vaccination remains valuable even when administered after sexual debut, as it may prevent infection with HPV types not yet encountered by the individual.
Expert Commentary
The findings from Kitano and Yoshida’s study represent a significant advancement in our understanding of HPV vaccine effectiveness in males. The use of propensity score matching strengthens the causal inference beyond what is typically possible in observational research, though limitations inherent to retrospective cohort design remain.
From a mechanistic perspective, the biological plausibility of these findings is well-established. HPV oncogenesis involves persistent infection with high-risk HPV types, leading to integration of viral DNA into the host genome and subsequent malignant transformation. By generating neutralizing antibodies against key HPV types, vaccination prevents initial infection and subsequent carcinogenic progression.
The consistent findings across age subgroups align with current ACIP (Advisory Committee on Immunization Practices) recommendations, which have increasingly emphasized sex-neutral HPV vaccination since 2019. However, global vaccination coverage in males remains suboptimal in many regions, and this study provides compelling evidence to support efforts aimed at improving uptake.
Potential limitations warrant consideration. The retrospective nature of the study introduces the possibility of residual confounding despite propensity score matching. Additionally, cancer outcomes may not manifest for decades following HPV infection, meaning that even the 10-year follow-up period may underestimate long-term vaccine effectiveness. Finally, the database may not capture all relevant covariates, including sexual behavior, smoking status, and other risk factors that influence HPV-related cancer development.
Despite these limitations, the magnitude of effect size observed (HR 0.54) substantially exceeds what would be expected from systematic bias alone, and the narrow confidence intervals reflect the study’s large sample size and statistical power.
Conclusion
This landmark retrospective cohort study provides robust evidence that 9-valent HPV vaccination significantly reduces the risk of HPV-related cancers in adolescent and young adult males. The 46% risk reduction observed overall, combined with consistent protective effects across age subgroups, supports the implementation of sex-neutral HPV vaccination strategies as a public health priority.
The findings have direct implications for clinical practice: healthcare providers should recommend HPV vaccination for all eligible males, understanding that benefits extend beyond prevention of genital warts to include substantial protection against multiple cancer types. From a policy perspective, these data strengthen the rationale for achieving high vaccination coverage in both sexes, which is essential for realizing the full population-level benefits of HPV immunization.
Future research should focus on long-term follow-up to assess lifetime cancer risk reduction, evaluation of vaccine effectiveness against specific cancer subtypes, and investigation of optimal vaccination schedules. Additionally, efforts to improve vaccine uptake, particularly among populations with historically lower coverage rates, will be critical to maximizing the public health impact of these findings.
Funding and Disclosures
This study was conducted using data from a global database. Specific funding sources were not detailed in the available study information. The authors reported no conflicts of interest relevant to this research.
References
1. Kitano T, Yoshida S. Nine-Valent Human Papillomavirus Vaccination and Related Cancers in Males. JAMA Oncol. 2026 Apr 9. PMID: 41954909.
2. WHO HPV Vaccine Position Paper. Weekly Epidemiological Record. 2022.
3. Centers for Disease Control and Prevention. HPV Vaccine Recommendations. MMWR. 2023.
4. Lei J, et al. HPV Vaccination and the Risk of Invasive Cervical Cancer. N Engl J Med. 2020.
