Sequence-Anchored Shared Tumor-Specific Epitopes for Pre-Manufactured HLA-Matched mRNA Cancer Vaccine Libraries: A Pan-Cancer Framework.

A single vaccine cannot prevent or treat all cancers; however, recurrent tumor-specific epitopes may facilitate the development of pre-manufactured, HLA-matched mRNA vaccines tailored for specific molecular subgroups. We define the shared tumor-specific epitope as a recurring peptide derived from a viral oncoprotein, a driver mutation, a frameshift, an altered protein C-terminus, or a fusion junction, and we employ a rigorous cancer-cell-only criterion: a target must be recurrent within a defined subgroup, absent from essential normal tissues at the peptide-HLA level, naturally presented on tumor cells, and sufficiently clonal to minimize immune escape. Under this criterion, we present fifteen sequence-anchored reference designs alongside one conceptual placeholder across thirteen candidates divided into four superclasses: viral oncoproteins (such as HPV16/18 E6 and E7 as attenuated antigenic reference designs; Merkel cell polyomavirus serving as a design-specific placeholder), recurrent driver neoepitopes (including KRAS G12/G13, IDH1 R132H, and H3 K27M), hematologic neoantigens (such as NPM1 Type A C-terminus; and a single CALR exon 9 construct encoding the shared novel C-terminus of types 1 and 2 mutations), and fusion junctions (notably EWS-FLI1 and BCR-ABL). Each open reading frame is anchored to a canonical accession with its documented event; representative ORFs are provided as reference designs, with the intended residue-level verification records. These sequence designs are intended as reference constructs and are not suitable as clinical-grade or manufacturing-ready products; they require independent residue-level validation and comprehensive safety assessments prior to laboratory or clinical application. The historical record of non-personalized vaccination-including HPV and hepatitis B prophylaxis, intravesical BCG, and unsuccessful tumor-associated antigen trials-frames both the potential and limitations of such approaches. The practical product is not a universal vaccine but rather a governed library aligned with specific genotype, viral etiology, HLA context, and clinical setting. Currently, none of these designs have established proof-of-benefit-tier evidence.