HPV T-cell epitope landscape: systematic mapping of distribution, conservation, and HLA promiscuity towards rational vaccine design
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Background
Human papillomavirus (HPV) drives both malignant and benign tumors, yet the current prophylactic vaccines remain type-restricted and are not optimized for T-cell induction. Evidence shows that T-cells can both block and clear viral infections, supporting T-cell-based vaccines. We compile a comprehensive list of T-cell epitopes, analyze specificity and immunodominance, and perform in silico analysis to investigate conserved and HLA promiscuous T-cell epitopes to support immune monitoring and to guide prophylactic and therapeutic pan-HPV vaccine design.
Methods
Functionally 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 HLA. Additionally, we assessed conservation of each epitope across 454 complete HPV reference genomes and predicted their HLA-promiscuity.
Results
We identified 485 unique epitopes (133 studies; 1,494 functional assays). E6 and E7 proteins exhibited the highest epitope density and immunogenicity (CD4+/CD8+ response rate of 0.25/0.20 and 0.21/0.29, respectively). L2, despite high conservation, yielded only one validated epitope. High-risk HPV, especially HPV16 and HPV18, dominated the epitope landscape (p<.001), and favored 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, with broader Class II allele restriction (OR 8.03; 95% CI 4.08-15.78; p<.001). In silico analysis showed epitopes in the capsid proteins L1/L2 and in high-risk HPV types were more conserved (p<.001). Conserved, immunodominant, and HLA-promiscuous epitopes were identified from existing data.
Conclusion
HPV epitope data are dominated by E6/E7, while conserved regions are underexplored, with L2 the most neglected. Epitope mapping and validation of conserved and HLA-promiscuous epitopes across broader HPV genomic datasets is critical for accurate assessment of cellular immunity to HPV and for rational design of next-generation vaccines.
