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Cross\u2010reactive CD4\n +<\/jats:sup>\n T\u00a0cells between A\/H1N1 and A\/H5N1 subtypes targeting internal and surface influenza proteins have been identified in humans, indicating some protection against severe and fatal A\/H5N1 infection.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n To detect T\u2010cell responses towards H1 and H5 viruses, we stimulated PBMCs from patients hospitalised with seasonal influenza A viruses, alongside healthy individuals, with overlapping peptide pools spanning hemagglutinin (HA) and neuraminidase (NA) of A\/Vietnam\/1203\/2004 (H5N1) and A\/New York\/18\/2009 (H1N1\u2010pdm09\u2010like) viruses.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Majority of acutely infected and healthy participants (100% and 75%, respectively) had detectable CD4\n +<\/jats:sup>\n and CD8\n +<\/jats:sup>\n T\u2010cell responses towards H1\u2010HA and H5\u2010HA, whereas 30\u201380% of individuals had detectable H5\u2010NA responses. H1 and H5 HA\u2010specific CD4\n +<\/jats:sup>\n T\u2010cell responses highly correlated, suggesting some level of cross\u2010reactivity between T\u2010cell responses directed against H1 and H5 subtypes. HA\u2010specific CD4\n +<\/jats:sup>\n T\u2010cell responses were increased in influenza patients compared to healthy participants. We found no differences in H1\u2010 and H5\u2010specific T\u00a0cell responses between those born pre\u2010 and post\u20101968, irrespective of infection status. Sequence alignment of H1 and H5 viruses identified high conservation in the HA2 stalk subunit (81.53%). CD4\n +<\/jats:sup>\n T\u2010cell immunity towards immunodominant HA\n 306\u2013318<\/jats:sub>\n epitope, restricted by several HLA\u2010DRB1 molecules, revealed limited cross\u2010reactivity between Group 1 and Group 2 HA\u2010subtypes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We define correlative H1\u2010 and H5\u2010specific CD4\n +<\/jats:sup>\n T\u2010cell responses during seasonal influenza A virus infection, likely reflecting some level of H1\/H5 T\u00a0cell cross\u2010reactivity.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/cti2.70118","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:53Z","timestamp":1785715253000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD4<\/scp>\n +<\/sup>\n T\u2010cell responses directed towards A\/H5N1\u2010derived haemagglutinin peptides increase in patients with seasonal influenza A virus infection"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4197-2573","authenticated-orcid":false,"given":"Lilith F","family":"Allen","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-5089","authenticated-orcid":false,"given":"Louise C","family":"Rowntree","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8427-9988","authenticated-orcid":false,"given":"Mitchell","family":"Jenzen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Immunity Program, Biomedicine Discovery Institute Monash University Clayton VIC Australia"},{"name":"Department of Human\u2010Centred Computing Monash University Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4437-2458","authenticated-orcid":false,"given":"Ruth R","family":"Hagen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2128-5127","authenticated-orcid":false,"given":"Nathan P","family":"Croft","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Immunity Program, Biomedicine Discovery Institute Monash University Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"James","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology Austin Health Heidelberg VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5142-7440","authenticated-orcid":false,"given":"Genevieve E","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia"},{"name":"Department of Infectious Diseases and Immunology Austin Health Heidelberg VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0532-8331","authenticated-orcid":false,"given":"Anthony W","family":"Purcell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Immunity Program, Biomedicine Discovery Institute Monash University Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3870-0796","authenticated-orcid":false,"given":"Patricia T","family":"Illing","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Immunity Program, Biomedicine Discovery Institute Monash University Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1368-8356","authenticated-orcid":false,"given":"Steven Y C","family":"Tong","sequence":"additional","affiliation":[{"name":"Victorian Infectious Diseases Service, The Royal Melbourne Hospital Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia"},{"name":"Department of Infectious Diseases University of Melbourne, at the Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen C","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine Monash University Melbourne VIC Australia"},{"name":"Monash Infectious Diseases, Monash Health and School of Clinical Sciences Monash University Clayton VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom C","family":"Kotsimbos","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine The Alfred Hospital Melbourne VIC Australia"},{"name":"Department of Medicine, Central Clinical School, The Alfred Hospital Monash University Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5111-6367","authenticated-orcid":false,"given":"Jason A","family":"Trubiano","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology Austin Health Heidelberg 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