Emergence of seasonal influenza A(H3N2) variants with immune escape potential warrants enhanced molecular and epidemiological surveillance for the 2025–2026 season
Bibliographic record
Abstract
Background: All of the major antigenic changes in influenza A(H3N2) viruses since 1968 have involved mutations at just nine amino acid positions, called cluster transition sites, surrounding the receptor binding region of the hemagglutinin surface protein. During the Northern Hemisphere (NH) 2024-2025 influenza season, A(H3N2) variants emerged with multiple parallel substitutions affecting cluster transition sites 135, 145, 158, and/or 189, with implications for the 2025-2026 season. Methods: Using >24,000 global A(H3) sequences between September 2024 and August 2025, we assessed the nature and frequency of amino acid mutations among emerging NH and Southern Hemisphere (SH) A(H3N2) variants relative to the 2024-2025 subclade J and updated 2025-2026 subclade J.2 vaccine reference strains. We contextualized based on historic amino acid variation among >210,000 global A(H3) sequences since 1968 and publicly available antigenic characterization data relative to 2024-2025 and 2025-2026 vaccine reference strains. Results: Virtually all circulating A(H3N2) viruses in 2024-2025 were subclade J.2. In Europe, about one-third had cluster transition site mutations, mostly T135A with S145N. In North America, more than two-thirds had cluster transition site mutations, including T135K or S145N, with a late-season increase in doubly mutated J.2.3 (N158K + K189R) and J.2.5 (S145N + N158K) subclades. The SH 2025 season showed an increase in J.2.3 and emergence of J.2.4 (T135K + K189R), including a further drifted J.2.4.1 variant with additional N158D and other mutations, recently renamed subclade K. A substantial proportion of J.2.3 and J.2.4 viruses are antigenically distinct from the 2025-2026 influenza vaccine. Conclusion: Influenza A(H3N2) variants with a combination of cluster transition site mutations emerged during the NH 2024-2025 season. A further drifted and vaccine-mismatched variant, called subclade K, arose during the SH 2025 season and is projected to predominate among A(H3N2) viruses for the NH 2025-2026 season. While mismatched vaccines can still provide protection, enhanced genetic, antigenic, and epidemiological (eg, vaccine effectiveness, disease burden) monitoring are warranted to inform risk assessment and response.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.010 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".