Should routine HPV vaccination programs include males 25-29 years? A systematic review and global meta-analysis.

BACKGROUND: Males aged 25-29 years represent the peak transmission group for human papillomavirus (HPV). However, they are often excluded from routine vaccination programs due to concerns regarding cost-effectiveness and limited efficacy data. This study synthesized evidence on vaccine efficacy and herd effects to support the potential expansion of HPV vaccination to this demographic. METHODS: This systematic review and meta-analysis searched PubMed, Embase, and the Cochrane Library from January 1, 2007, to February 1, 2025. We included randomized controlled trials and observational studies that reported on the efficacy of the 4vHPV vaccine against incident HPV infections (4vHPV-type [6/11/16/18] or any HPV) in males, as well as herd effects on anogenital warts (AGW) in unvaccinated males aged 25-29 years following female vaccination. Exclusions comprised pediatric, HIV, and female-only cohorts, non-4vHPV vaccines, and immunogenicity-only reports. Two reviewers independently extracted summary-level data, and discrepancies were resolved by a third reviewer. The primary outcomes were pooled relative risks (RRs) for HPV infection and AGW incidence, calculated using DerSimonian-Laird random-effects models. (PROSPERO: CRD420251104471) RESULTS: From 3,024 screened records, 28 studies (2 RCTs, 26 observational; n = 68,113,157 participants) were analyzed. Direct vaccination significantly reduced 4vHPV-type infections among males aged 13-26 years (RR = 0.35, 95% CI: 0.18-0.65; I2 = 85.4%). Extrapolated to males aged 25-29 years (baseline risk = 35%), this conferred an absolute risk reduction (ARR) of 22.75% (number needed to treat [NNT] = 4, 95% CI: 3-5). Herd effects analysis demonstrated that when female vaccination coverage (FVC) reached ≥50%, unvaccinated males aged 25-29 years experienced a 37% reduction in AGW incidence over 5-8 years (RR = 0.63, 95% CI: 0.48-0.84; I2 = 93.7%). This protection was significantly stronger than that in males aged 30-39 years (ΔRR = 0.05, p = 0.03) and increased cumulatively by 6% annually (p < 0.001). No such herd protection occurred with FVC < 50% (RR = 1.13-1.36). CONCLUSIONS: This study demonstrates that extending HPV vaccination to males aged 25-29 years provides both individual and population-level benefits, particularly in settings with suboptimal female coverage. These findings support the inclusion of this demographic in vaccination programs and suggest that revising current age-restrictive policies could contribute to global efforts to eliminate HPV-related diseases. Future research should focus on real-world data to further strengthen the evidence base.