John Huddleston🧵 This recent article by Edward Chen describes why we think the current flu season has been so intense (https://www.nature.com/articles/d41586-026-00061-6). A new genetic variant in the subtype H3N2 named “clade K” appears to be the cause of most recent cases. This variant has 11 amino acid mutations relative to the current vaccine strain. Edward asked me if this was an usually high number of mutations compared to past seasons. I didn’t know the answer, so I ran the following analysis to find out.
This figure shows the pairwise hemagglutinin (HA) amino acid distance between each season’s H3N2 egg-passaged vaccine strain and a random sample of ~100-300 H3N2 strains circulating in the same season. Points show the median pairwise distance per season and error bars show the first and third quartile. The horizontal rule shows the average distance across all seasons. Northern Hemisphere seasons span from October 1 to April 1. Southern Hemisphere seasons span from April 1 to October 1.
The view above shows that the _number_ of mutations between current H3N2 strains and the vaccine is not historically high (the last pink dot). But, the _increase_ of 5 mutations since the previous season with the same vaccine (the second to last pink dot) is unprecedented since 2006.
As Jiaojiao Liu and others from Scott Hensley’s lab note in their recent preprint (https://www.medrxiv.org/content/10.64898/2026.01.05.26343449v1.full-text), the nature of these new mutations also matters. Most of the recent mutations occur in parts of H3N2’s hemagglutinin that could allow K viruses to escape our existing immunity. Fortunately, Liu et al. show that this season’s vaccine still may protect us against the K variant, despite the many new mutations.
Antibodies elicited by the 2025-2026 influenza vaccine in humans
A new H3N2 variant (named subclade K) possesses several key hemagglutinin substitutions and is circulating widely during the 2025-2026 influenza season. In this report, we completed experiments to determine if the 2025-2026 seasonal influenza vaccine elicits antibodies in humans that recognize this variant. We find that H3N2 subclade K viruses are antigenically advanced; however, the 2025-2026 seasonal influenza vaccine elicited antibodies in many individuals that efficiently recognized these viruses. Thus, the current seasonal influenza vaccine will likely be somewhat effective at preventing H3N2 subclade K virus infections. ### Competing Interest Statement S.E.H. is a co-inventor on patents that describe the use of nucleoside-modified mRNA as a vaccine platform. S.E.H reports receiving consulting fees from Sanofi, Pfizer, Lumen, Novavax, and Merck. ### Funding Statement This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00015 (S.E.H.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Institutional Review Board of the University of Pennsylvania under protocol #849398. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data are provided in this manuscript.
The figure above is based on 9,749 sequences and metadata collected through December 17, 2025 and available on GISAID with https://doi.org/10.55876/gis8.260112df. Thank you to the many people who worked hard to provide these data to support analyses like this.