Assessment of human immunity to A/H3N2 influenza subclade K during 2025 emergence

BACKGROUND: Seasonal influenza causes significant morbidity and mortality annually. In 2025, the genetically divergent A/H3N2 K subclade (J.2.4.1) emerged with substantial haemagglutinin mutations. However, despite suggested antigenic escape, UK vaccine effectiveness estimates and epidemiological data demonstrated a relatively normal influenza season across 2025-26. We examined neutralising antibody responses in human cohorts to investigate existing and vaccine-induced immunity to K clade viruses. METHODS: We characterised the antigenic relationships of a selection of A/H3N2 viruses spanning recent evolution including a subclade K virus using antigenic cartography, followed by serological antibody profiling of four human cohorts from the United Kingdom and Norway using microneutralisation (MN) and haemagglutination inhibition (HAI) assays. FINDINGS: Antigenic cartography from single-infection ferret antisera suggests significant antigenic drift from the vaccine strains. MN and HAI titres from 243 individuals across 4 human cohorts (ages 1-105 years) were measured for comparison. The 2025/26 Northern Hemisphere seasonal inactivated egg-derived trivalent influenza vaccine (eTIV, with J.2 A/H3N2) significantly boosted MN and HAI titres against all A/H3N2 viruses tested, including a subclade K virus (p < 0.001). Furthermore, serological profiles of cohorts stratified by age groups (≤5, >5-≤15, >20-≤25, >25-