Seasonal vaccine-induced immunity shows preserved cross-reactivity to H3N2 subclade K in adults

BACKGROUND: Influenza A subclade K viruses caused high infection rates in the 2025/2026 Northern Hemisphere season, raising concerns about antigenic drift and reduced vaccine effectiveness. METHODS: We measured antibody responses in matched human pre- and post-vaccination sera, selected from two observational cohort studies of adults, against both a vaccine-like as well as subclade K isolates. FINDINGS: Pre-existing immunity to subclade K variants was noted with seasonal influenza vaccination further boosting titres two-fold against subclade K and three-fold against the vaccine-like strain, consistent with limited antigenic divergence between subclade K isolates and the vaccine. These findings contrast with ferret-based predictions of marked antigenic drift and align with the observed vaccine effectiveness in adults. INTERPRETATION: Our results underscore the importance of incorporating human serologic data in influenza surveillance to better inform vaccine strain selection and anticipate vaccine performance in immunologically experienced populations. FUNDING: NIAID Centers for Excellence in Influenza Research and Response (75N93021C00014); NIAID VIVA HIPC (U19 AI168631); Mount Sinai Center for Vaccine Research and Pandemic Preparedness; institutional support from the Mount Sinai Center for Vaccine Research and Pandemic Preparedness and the Medical University of Vienna.