Abstract
Influenza A virus antigenic drift forces annual vaccine reformulation, motivating the search for conserved epitope candidates that could support broadly protective vaccines. We systematically screened influenza A virus sequences (H1N1, H3N2, H5N1; nine viral proteins) to define 98 conserved candidate regions, 38 of which were identical across the H1N1, H3N2, and H5N1 consensus sequences, all in the polymerase complex and nucleoprotein (PB2, PB1, PA, NP), whereas the ten surface-glycoprotein (HA/NA) candidates were subtype-specific. We then benchmarked two protein-language-model (ESM-2) features against alignment conservation. Group-masked log-probability correlated moderately with MSA conservation (Spearman rho = 0.25 to 0.39 for HA) but provided no incremental value for T-cell epitope discrimination (change in AUROC +0.004, p = 0.46); attention-derived contact-density was not a valid solvent-accessibility proxy. A curated antibody-epitope benchmark (22 clusters, 5 neutralization-supported) was underpowered for a high-confidence B-cell test. We document data-quality and reproducibility pitfalls (length heterogeneity, coordinate mapping, and pseudoreplication) and release the auditable benchmark. These results provide an auditable candidate resource and show that, in the evaluated benchmarks, ESM-2 sequence scores did not improve epitope prioritization beyond alignment-derived conservation.
Competing Interest Statement
The authors have declared no competing interest.
Source:
Link: https://www.biorxiv.org/content/10.64898/2026.08.16.745106v1
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