Reduced T cell epitope cross-conservation and immunogenic potential is associated with emergence of a dominant influenza subclade K in 2025.

Subclade K is a newly emergent influenza A/H3N2 strain that became the dominant strain circulating globally; more than 90% of influenza A virus (IAV) cases in 2025-26 were subclade K. While seasonal vaccines elicited measurable cross-reactive hemagglutination inhibition (HI) and neutralizing antibody responses against the new strain were deemed to be protective, T cells contribute substantially to protection against infection and severe disease. T cell epitopes that are conserved between vaccine strains and circulating strains may have a protective effect. We hypothesized that mutations in the HA antigen introduced by viral evolution resulted in the loss of some cross-conserved T cell epitopes and that this loss may have contributed to the emergence of subclade K. Using a new immunoinformatics tool, EpiCC, we assessed T cell epitope cross-conservation between subclade K, other circulating H3N2 strains, and the most recent seasonal vaccine strains. Evaluation of 706 H3N2 HA sequences demonstrated a 10% reduction in cross-conserved T cell epitope content between seasonal vaccines, circulating strains and subclade K. Decreased cross-conservation may signal the emergence of new flu strains. Proactive analysis of cross-conserved T cell epitopes may improve vaccine selection. Loss of T cell epitopes could also reduce the efficacy of new subclade K influenza vaccines in fall 2026.