{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:42:06Z","timestamp":1791258126976,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Background: Influenza A(H3N2) viruses remain a major public health concern due to their rapid antigenic evolution and association with severe disease, particularly among high-risk populations. During the 2025\u20132026 influenza season, a marked epidemiological shift was observed in Europe, with the emergence and predominance of the A(H3N2) subclade K (J.2.4.1). Objectives: This narrative review aims to provide an integrated overview of the epidemiology, evolutionary dynamics, and public health implications of subclade K, with a particular focus on its impact on vaccine effectiveness, in comparison with the 2024\u20132025 influenza season. Methods: A non-systematic literature review was conducted using major scientific databases and official public health sources, including WHO and ECDC reports. Recent surveillance data, genomic analyses, and epidemiological updates were included. Given the rapidly evolving evidence base, selected preprint studies were also considered and interpreted with caution. Results: The 2025\u20132026 influenza season in Europe was characterized by a relative genetic convergence, with subclade K accounting for the majority of A(H3N2) sequences. This variant demonstrated a clear selective advantage and was associated with an earlier and more intense epidemic peak. Molecular analyses indicate the accumulation of multiple mutations in the hemagglutinin protein, particularly within key antigenic sites, contributing to immune escape. These evolutionary changes have important implications for vaccine effectiveness, with current estimates suggesting moderate protection against infection but preserved effectiveness against severe outcomes. Antigenic mismatch, manufacturing constraints, and host-related factors further contribute to reduced vaccine performance. Conclusions: The emergence and rapid spread of subclade K highlight the dynamic nature of influenza virus evolution and its impact on public health. Continuous genomic surveillance and timely vaccine updates remain essential. Despite suboptimal effectiveness against infection, influenza vaccination continues to provide significant protection against severe disease and should remain a cornerstone of prevention strategies.<\/jats:p>","DOI":"10.3390\/pathogens15050474","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:09:33Z","timestamp":1777388973000},"page":"474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Influenza A(H3N2) Subclade K: Epidemiology, Molecular Evolution and Vaccine Effectiveness in Europe"],"prefix":"10.3390","volume":"15","author":[{"given":"Irene","family":"Scarvaglieri","sequence":"first","affiliation":[{"name":"Unit of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2221-6286","authenticated-orcid":false,"given":"Maria Antonia","family":"De Francesco","sequence":"additional","affiliation":[{"name":"Highly Specialized Laboratory, ASST Spedali Civili of Brescia, 25123 Brescia, Italy"},{"name":"Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Alberti","sequence":"additional","affiliation":[{"name":"Unit of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4327-7305","authenticated-orcid":false,"given":"Federico","family":"Cesanelli","sequence":"additional","affiliation":[{"name":"Unit of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Salvi","sequence":"additional","affiliation":[{"name":"Unit of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7366-871X","authenticated-orcid":false,"given":"Giorgio","family":"Tiecco","sequence":"additional","affiliation":[{"name":"Unit of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9161-7804","authenticated-orcid":false,"given":"Francesco","family":"Castelli","sequence":"additional","affiliation":[{"name":"Unit of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1452-9100","authenticated-orcid":false,"given":"Eugenia","family":"Quiros-Roldan","sequence":"additional","affiliation":[{"name":"Unit of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy"},{"name":"Department of Global Public Health, Karolinska Institutet, 171 76 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1001\/jama.2025.25903","article-title":"Influenza A(H3N2) Subclade K Virus: Threat and Response","volume":"335","author":"Zambon","year":"2026","journal-title":"JAMA"},{"key":"ref_2","unstructured":"(2026, April 02). ECDC Threat Assessment Brief. Assessing the Risk of Influenza for the EU\/EEA in the Context of Increasing Circulation of A(H3N2) Subclade K. Available online: https:\/\/www.ecdc.europa.eu\/sites\/default\/files\/documents\/Threat%20Assessment%20Brief%20-%20Assessing%20the%20risk%20of%20increasing%20circulation%20of%20A%28H3N2%29%20subclade%20K.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2600109","DOI":"10.2807\/1560-7917.ES.2026.31.7.2600109","article-title":"Influenza vaccine effectiveness from nine studies during drifted A(H3N2) subclade K predominance, Europe, September 2025 to January 2026","volume":"31","author":"Lucaccioni","year":"2026","journal-title":"Eurosurveillance"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"669","DOI":"10.2105\/AJPH.2019.305557","article-title":"Fifty Years of Influenza A(H3N2) Following the Pandemic of 1968","volume":"110","author":"Jester","year":"2020","journal-title":"Am. J. Public Health"},{"key":"ref_5","unstructured":"Rogers, K. (2025). 1968 flu pandemic. Encyclopedia Britannica, Encyclop\u00e6dia Britannica, Inc.. Available online: https:\/\/www.britannica.com\/event\/1968-flu-pandemic."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e952952","DOI":"10.12659\/MSM.952952","article-title":"Editorial: Increased Respiratory Infections in the 2025\u20132026 Influenza Season and the (A)H3N2 Virus, a Past Cause of Pandemic Influenza","volume":"32","author":"Parums","year":"2026","journal-title":"Med. Sci. Monit."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrmicro.2017.118","article-title":"The evolution of seasonal influenza viruses","volume":"16","author":"Petrova","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2600070","DOI":"10.2807\/1560-7917.ES.2026.31.6.2600070","article-title":"Cross-sectional study on protective antibodies against influenza A virus subtypes and cross-protection against influenza A(H3N2) subclade K, Portugal, August 2025","volume":"31","author":"Guiomar","year":"2026","journal-title":"Eurosurveillance"},{"key":"ref_9","first-page":"1292","article-title":"Seasonal Influenza Virus Activity during the 2024\u20132025 Season: Based on the Republic of Korea\u2019s National Pathogen Surveillance Data","volume":"18","author":"Lee","year":"2025","journal-title":"Jugan Geongang Gwa Jilbyeong"},{"key":"ref_10","unstructured":"European Centre for Disease Prevention and Control (2025). Influenza Virus Characteristics, Week 40 2024 to Week 33 2025, EU\/EEA, ECDC. Available online: https:\/\/www.ecdc.europa.eu\/en\/publications-data\/influenza-virus-characteristics-week-40-2024-week-33-2025."},{"key":"ref_11","unstructured":"(2026, April 02). European Respiratory Virus Surveillance Summary. Available online: https:\/\/erviss.org\/."},{"key":"ref_12","unstructured":"(2026, April 02). RespiVirNet, Week 09, 2026. Available online: https:\/\/www.epicentro.iss.it\/sorveglianza-infezioni-respiratorie-acute\/rapporto."},{"key":"ref_13","first-page":"2500992","article-title":"Interim vaccine effectiveness against influenza virus among outpatients, France, October 2025 to January 2026","volume":"31","author":"Blanquart","year":"2026","journal-title":"Eurosurveillance"},{"key":"ref_14","unstructured":"(2026, April 02). UKHSA, National Flu and COVID-19 Surveillance Report Week 13, 2026, Available online: https:\/\/www.gov.uk\/government\/statistics\/national-flu-and-covid-19-surveillance-reports-2025-to-2026-season\/national-flu-and-covid-19-surveillance-report-26-march-2026-week-13."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s11357-026-02108-y","article-title":"Is the emerging influenza A(H3N2) K subclade a specific threat for older adults?","volume":"48","author":"Quarleri","year":"2026","journal-title":"GeroScience"},{"key":"ref_16","unstructured":"(2026, April 02). WHO Seasonal Influenza\u2014Global Situation. Available online: https:\/\/www.who.int\/emergencies\/disease-outbreak-news\/item\/2025-DON586."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102949","DOI":"10.1016\/j.tmaid.2025.102949","article-title":"Converging Influenza Threats: Seasonal A(H3N2) (including subclade K) Dynamics and the Persistent Pandemic Risk of A(H5N1)","volume":"69","year":"2026","journal-title":"Travel Med. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.chom.2010.05.009","article-title":"Influenza virus evolution, host adaptation, and pandemic formation","volume":"7","author":"Taubenberger","year":"2010","journal-title":"Cell. Host Microbe"},{"key":"ref_19","unstructured":"CDC (2026, April 02). How Flu Viruses Can Change: \u2018Drift\u2019 and \u2018Shift\u2019, Available online: https:\/\/www.cdc.gov\/flu\/php\/viruses\/change.html."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1089\/vim.2017.0141","article-title":"Influenza virus: Dealing with a drifting and shifting pathogen","volume":"31","author":"Kim","year":"2018","journal-title":"Viral Immunol."},{"key":"ref_21","first-page":"1","article-title":"Influenza antigenic drift: What is the driving force?","volume":"6","author":"Wang","year":"2010","journal-title":"Cellscience"},{"key":"ref_22","unstructured":"Tankeshwar, A. (2026, April 02). Antigenic Drift and Antigenic Shift in Influenza Virus. Microbe Online, Available online: https:\/\/microbeonline.com\/antigenic-shift-antigenic-drift."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6852","DOI":"10.1016\/j.vaccine.2007.07.027","article-title":"Influenza vaccine: The challenge of antigenic drift","volume":"25","author":"Carrat","year":"2007","journal-title":"Vaccine"},{"key":"ref_24","unstructured":"World Health Organization (2026, April 02). Candidate Vaccine Viruses and Potency Testing Reagents. Available online: https:\/\/www.who.int\/teams\/global-influenza-programme\/vaccines\/who-recommendations\/candidate-vaccine-viruses."},{"key":"ref_25","unstructured":"World Health Organization (2026, April 02). Global Influenza Surveillance and Response System (GISRS). Available online: https:\/\/www.who.int\/initiatives\/global-influenza-surveillance-and-response-system."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.chom.2025.12.006","article-title":"Molecular basis of 60 years of antigenic evolution of human influenza A(H3N2) virus neuraminidase","volume":"34","author":"Rosu","year":"2026","journal-title":"Cell Host Microbe"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e01070-14","DOI":"10.1128\/mBio.01070-14","article-title":"Antigenic variation of clade 2.1 H5N1 virus is determined by a few amino acid substitutions immediately adjacent to the receptor binding site","volume":"5","author":"Koel","year":"2014","journal-title":"mBio"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.virol.2013.07.035","article-title":"Structural basis for the divergent evolution of influenza B virus hemagglutinin","volume":"446","author":"Ni","year":"2013","journal-title":"Virology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2211616119","DOI":"10.1073\/pnas.2211616119","article-title":"Substitutions near the HA receptor binding site explain the origin and major antigenic change of the B\/Victoria and B\/Yamagata lineages","volume":"119","author":"Rosu","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","first-page":"281","article-title":"Emergence of seasonal influenza A(H3N2) variants with immune escape potential warrants enhanced molecular and epidemiological surveillance for the 2025\u20132026 season","volume":"10","author":"Sabaiduc","year":"2025","journal-title":"J. Assoc. Med. Microbiol. Infect. Dis. Can."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2600111","DOI":"10.2807\/1560-7917.ES.2026.31.7.2600111","article-title":"Influenza A(H3N2) subclade K (J.2.4.1) viruses associated with a surge at a university health clinic, Arizona, the United States, November to early December 2025","volume":"31","author":"Scotch","year":"2026","journal-title":"Eurosurveillance"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1001\/jama.2026.2173","article-title":"Vaccine-Elicited Antibody Responses to Influenza A(H3N2) Subclade K","volume":"335","author":"Wang","year":"2026","journal-title":"JAMA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1056\/NEJMp2600395","article-title":"Antigenic Drift and Antivaccine Shift in the 2025-2026 Influenza Season","volume":"394","author":"Rasmussen","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2500854","DOI":"10.2807\/1560-7917.ES.2025.30.46.2500854","article-title":"Early influenza virus characterisation and vaccine effectiveness in England in autumn 2025, a period dominated by influenza A(H3N2) subclade K","volume":"30","author":"Kirsebom","year":"2025","journal-title":"Eurosurveillance"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wilson, A., Lerman, B., Ramsamooj, R., Mischka, J., Ehrenhaus, J., Aracena, A., Figueroa, Y., Farrugia, K., Gonzalez-Reiche, A.S., and Nardulli, J. (2026). Seasonal vaccine-induced immunity shows preserved cross-reactivity to H3N2 subclade K in adults. medRxiv, 2026.02.18.26346502.","DOI":"10.64898\/2026.02.18.26346502"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Liu, J., Gang, S., Kikawa, C., Rodriguez, A.J., Li, S.H., Ye, N., Griffiths, T., Drapeau, E.M., Atkinson, R.K., and Loes, A.N. (2026). Mapping the specificity of H3N2 strain-specific and cross-reactive human neutralizing antibodies elicited by the 2025\u20132026 influenza vaccine. medRxiv, 2026.02.20.26346746.","DOI":"10.64898\/2026.02.20.26346746"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Branda, F., Petrosillo, N., Ceccarelli, G., Scarpa, F., Giovanetti, M., and Ciccozzi, M. (2026). Influenza A(H3N2) Subclade K (J.2.4.1): Molecular Characterization, Antigenic Divergence, and Global Spread During the 2025\/26 Season. Infect. Dis. Rep., 18.","DOI":"10.3390\/idr18020037"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Quiros-Roldan, E., Sottini, A., Natali, P.G., and Imberti, L. (2024). The Impact of Immune System Aging on Infectious Diseases. Microorganisms, 12.","DOI":"10.3390\/microorganisms12040775"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.it.2017.08.003","article-title":"From Original Antigenic Sin to the Universal Influenza Virus Vaccine","volume":"39","author":"Henry","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_40","unstructured":"EUROSTAT (2026, April 02). Influenza Statistics. Available online: https:\/\/ec.europa.eu\/eurostat\/statistics-explained\/index.php?title=Influenza_statistics#Influenza_vaccination_rates_%E2%80%93_based_on_vaccination_programme_data."},{"key":"ref_41","unstructured":"EMA (2026, April 02). EU Recommendations for 2026\/2027 Seasonal Flu Vaccine Composition. Available online: https:\/\/www.ema.europa.eu\/en\/news\/eu-recommendations-2026-2027-seasonal-flu-vaccine-composition."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/5\/474\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:34:35Z","timestamp":1777390475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/5\/474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":41,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["pathogens15050474"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15050474","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,28]]}}}