Toward next-generation therapeutic HPV vaccines: A review on expanding the antigen repertoire and an integrated bioinformatics selection framework

For successful clinical translation of therapeutic human papillomavirus (HPV) vaccines, optimizing antigen selection is key to enhancing efficacy. Traditional E6/E7 targets are limited by heterogeneous tumor expression. This review advocates expanding the antigen repertoire to include tumor-specific neoantigens in next-generation vaccines. We systematically evaluate established HPV therapeutic antigens and vaccine platforms, and comprehensively explore the frontier of novel antigens, advanced screening technologies, and recent vaccine innovations. Central is a bioinformatics-guided antigen selection framework spanning multi-omics analysis, immunogenicity prediction, and vaccine design. Key selection parameters - including antigen clonality, expression level, major histocompatibility complex (MHC) binding affinity and stability, and immunogenic potential - are critically assessed alongside state-of-the-art computational tools. By proposing standardized selection criteria and optimization strategies, this review aims to provide a roadmap for developing more potent and broadly effective therapeutic vaccines, ultimately bridging the gap between the molecular etiology of HPV-associated cancers and successful therapeutic discovery.