Background: Human papillomavirus (HPV) vaccine effectiveness against HPV-related head and neck cancer (HNC) remains unclear. We aimed to quantify the association between HPV vaccination, oral HPV infection, and HNC.
Methods: We performed a systematic review and meta-analysis that was registered in PROSPERO (CRD420261366821). We searched Medline, Embase, CINAHL, and Web of Science from January 2000 to April 2026, for studies of HPV vaccination in oral HPV infection and HNC. We assessed risk of bias (RoB) with Cochrane RoB 2.0 for randomized trials and ROBINS-I for non-randomized studies. We generated pooled risk ratios (RR) with random effects models, conducted meta-regression for effect modifiers, and evaluated the certainty of evidence using Grading of Recommendations Assessment, Development, and Evaluation (GRADE).
Findings: Out of 470 unique citations, 42 studies met eligibility criteria. Twenty-three studies including 32,595 participants investigated oral HPV infection. High certainty evidence demonstrated that HPV vaccination prevented oral HPV-16/HPV-18 infection [RR: 0.16, 95% confidence interval (CI): 0.08, 0.32; absolute risk reduction (ARR): 0.9% (95% CI: 0.7%, 1%)] and moderate certainty evidence suggested that HPV vaccination prevented oral HPV-16/HPV-18 infection when there was at least 40% vaccine coverage amongst females [RR = 0.35 (95% CI: 0.21, 0.57); ARR: 1.1% (95% CI: 0.7%, 1.3%)]. Low certainty evidence from over 2 million participants suggested that HPV vaccination prevents HNC in females [RR: 0.21 (95% CI: 0.11, 0.39); ARR: 7.7/100,000 (95% CI: 6/100,000, 8.7/100,000)] and very low certainty evidence suggested that HPV vaccination may prevent HNC in males.
Interpretation: HPV vaccination probably prevents oral HPV infection when at least 40% of females are vaccinated, and may reduce HNC in women. The effect of HPV vaccination to prevent HNC amongst men is uncertain: this may be secondary to the low HPV vaccination rate amongst males and is urgently troublesome since oropharyngeal cancer is rising in prevalence globally.
