Adjuvant HPV Vaccination and Survival in Oropharyngeal Squamous Cell Carcinoma: An Exploratory Analysis of a Real‐World Database

ABSTRACT Objective Childhood HPV vaccination reduces oropharyngeal cancer (OPC) incidence, but evidence regarding vaccination after HPV exposure or OPC diagnosis remains limited. While benefits are documented in cervical dysplasia, anogenital cancers, and laryngeal papillomatosis, the impact on OPC outcomes is unknown. Methods Using the prospective TrinetX database, OPC patients were stratified by HPV vaccination status. Vaccinated patients were divided into three cohorts: vaccinated before OPC diagnosis, within 1 year after diagnosis, and at any timepoint. Cohorts were propensity‐matched with unvaccinated controls by age, race, ethnicity, sex, and cancer stage. Survival outcomes were assessed at 2, 5, and > 5 years post‐diagnosis using absolute risk reduction and Kaplan–Meier analyses. Results Propensity matching yielded 162 patients vaccinated at any time, 24 vaccinated within 1 year post‐diagnosis, and 79 vaccinated pre‐diagnosis, with equal matched controls showing no demographic differences. Women predominated among those vaccinated before OPC diagnosis (73%), while men comprised 80% of those vaccinated after diagnosis. HPV vaccination was associated with improved overall survival at 2 years (97% vs. 91%, p = 0.29), 5 years (97% vs. 89%, p = 0.019), and > 5 years (93% vs. 74%, p = 0.0003) for the vaccinated‐anytime cohort versus never‐vaccinated patients, translating to 5.14% absolute risk reduction at 5 years. Trends persisted but lacked statistical significance in pre‐ and post‐diagnosis vaccination subgroups. Conclusion HPV vaccination after HPV exposure was associated with improved survival in OPC patients. However, imperfect HPV ascertainment, small vaccinated cohorts, and potential selection bias, including a healthy vaccinee effect, preclude causal inference, and this association should not be interpreted as evidence of a therapeutic effect. Prospective and randomized clinical trials are needed to determine whether adjuvant HPV vaccination confers a true survival benefit in OPC. Given the low morbidity of therapy and high potential survival impact, a clinical trial is warranted. Level of Evidence 3.