{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T09:36:28Z","timestamp":1774949788773,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Seasonal influenza A evolves quickly through mutations in haemagglutinin (HA) and neuraminidase (NA), which can reduce vaccine match and lower protection. Many sequence-only models do not link codon-level mutations to three-dimensional (3D) protein context and long-term evolutionary signals within one scoring framework. This study presents TRIAD-Influenza (TRIAD: Token\u2013Residue\u2013Integrated Architecture for Drift), a multi-view transformer that combines (i) codon- and residue-level sequence representations, (ii) structure-derived residue interaction features from predicted HA\/NA models, and (iii) an embedding-space phylogeny that captures cluster and drift context. The pipeline curates more than 3\u00d7105 paired HA\/NA coding sequences from the NCBI Virus resource (2010\u20132024) using strict quality control and codon-aware alignment and predicts 3D structures for nearly all unique HA and NA proteins to build contact graphs and surface\/stability descriptors. TRIAD-Influenza outputs a continuous, structure-aware risk score for each HA\/NA pair and produces interpretable mutation hotspot maps using gradient saliency and a contact-weighted mutation risk index (CMRI). On rolling-origin temporal cross-validation and for a temporally held-out internal test window with strong class imbalance (\u223c3.4% high-risk), the model shows strong ranking performance (AUROC \u22480.89; AUPRC \u22480.44; Brier score =0.069) while operating at surveillance speed (median latency \u22481.6 ms per HA\/NA pair). External validation on independent GISAID\/Nextstrain cohorts (2023\u20132024; 5000 isolates) preserves discrimination (AUROC \u22480.85\u20130.86). Predicted risk scores correlate with experimental haemagglutination inhibition (HI) antigenic distances (Spearman \u03c1 up to \u22480.82 at the virus-aggregated level), and CMRI hotspots enrich known epitope and deep mutational scanning escape residues (odds ratios \u22482.7\u20133.6). Overall, token\u2013residue\u2013phylogeny coupling enables rapid, structure-aware prioritisation of emerging influenza A HA\/NA sequences and delivers compact hotspot maps for expert review and targeted experiments.<\/jats:p>","DOI":"10.3390\/v18040421","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:03Z","timestamp":1774878063000},"page":"421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-View Transformers for Structure-Aware HA\u2013NA Drift Risk Scoring and Mutation Hotspot Mapping"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1027-2419","authenticated-orcid":false,"given":"Pankaj","family":"Agarwal","sequence":"first","affiliation":[{"name":"Centre for Intelligent Cloud Computing, COE for Advanced Cloud, Multimedia University, Melaka 75450, Malaysia"},{"name":"School of Engineering and Technology, K.R. Mangalam University, Sohna 122103, Haryana, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5151-2300","authenticated-orcid":false,"given":"Sumendra","family":"Yogarayan","sequence":"additional","affiliation":[{"name":"Centre for Intelligent Cloud Computing, COE for Advanced Cloud, Multimedia University, Melaka 75450, Malaysia"},{"name":"Faculty of Information Science and Technology, Multimedia University (MMU), Melaka 75450, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0052-4870","authenticated-orcid":false,"given":"Md. Shohel","family":"Sayeed","sequence":"additional","affiliation":[{"name":"Centre for Intelligent Cloud Computing, COE for Advanced Cloud, Multimedia University, Melaka 75450, Malaysia"},{"name":"Faculty of Information Science and Technology, Multimedia University (MMU), Melaka 75450, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8476-8364","authenticated-orcid":false,"given":"Rupesh Kumar","family":"Tipu","sequence":"additional","affiliation":[{"name":"School of Engineering and Technology, K.R. Mangalam University, Sohna 122103, Haryana, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/S0140-6736(17)33293-2","article-title":"Estimates of global seasonal influenza-associated respiratory mortality: A modelling study","volume":"391","author":"Iuliano","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrd4529","article-title":"Advances in the development of influenza virus vaccines","volume":"14","author":"Krammer","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/s41577-019-0143-6","article-title":"The human antibody response to influenza A virus infection and vaccination","volume":"19","author":"Krammer","year":"2019","journal-title":"Nat. Rev. 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