HPV T-cell epitope landscape: systematic mapping of distribution, conservation, and HLA promiscuity towards rational vaccine design

BackgroundHuman papillomavirus (HPV) drives both malignant and benign tumors. Current prophylactic vaccines remain type-restricted, are not optimized for T-cell induction, and have not been efficacious therapeutically. T-cells can both block and control viral infections, supporting T-cell-based vaccines. We compile a comprehensive list of the currently known T-cell epitopes. We analyze their distribution and immunodominance and perform in silico analysis to further investigate conservation and HLA-promiscuity, to guide future epitope mapping, support immune monitoring, and to guide prophylactic and therapeutic pan-HPV vaccine design. MethodsFunctionally validated HPV T-cell epitopes were curated from the Immune Epitope Database (IEDB), filtered by length, HLA restriction, and immunogenicity. Epitopes were mapped across viral proteins, genotypes and HLAs. Additionally, we assessed conservation of each epitope across 454 distinct complete HPV genomes and predicted their HLA-promiscuity. Results485 unique functionally validated HPV epitopes have been described (133 studies; 1,494 functional assays), originating from heterogeneous study contexts, including healthy donors, HPV-positive patients, and vaccination studies. Consistent with the study focus and viral biology, E6 and E7 proteins account for >60% of known HPV epitopes despite accounting for [~]10% of the viral proteome. L2 has so far yielded only one validated epitope despite being conserved. High-risk HPV types, especially HPV16 and HPV18, were the most studied (p<.001), and were enriched for CD8 epitopes (OR 6.18; 95% CI 3.40-11.22; p<.001). Epitopes were restricted by 27 Class I and 21 Class II HLA alleles. In silico analysis indicated differences in epitope conservation between structural and non-structural proteins, and between high-risk and low-risk HPV types. Conserved, immunodominant, and HLA-promiscuous epitopes were highlighted from existing data. ConclusionThis systematic analysis describes the dominance of E6/E7 in the reported HPV T-cell epitope landscape and quantitatively reveals major gaps in experimentally validated epitopes within conserved regions, particularly in L2. Addressing these gaps will be essential for a comprehensive assessment of cellular immunity and for rational next-generation HPV vaccine design.