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Human infections with avian and bovine origin H5N1 influenza viruses have been documented, raising concern that these viruses may cause a pandemic. Therefore, using a ferret model, we evaluated the impact of preexisting, infection-elicited immunity on susceptibility to H5N1 infection and on severity of disease. Preexisting immunity to the 2009 pandemic H1N1 influenza virus prevented severe H5N1 disease and reduced susceptibility to infection through direct contact with an infected donor ferret. These studies demonstrate that preexisting immunity to influenza viruses, especially the 2009 pandemic H1N1 virus, is a barrier to infection and disease caused by clade 2.3.4.4b H5N1 viruses.<\/jats:p>","DOI":"10.1126\/scitranslmed.adw4856","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T17:58:25Z","timestamp":1753293505000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":24,"title":["Preexisting immunity to the 2009 pandemic H1N1 virus reduces susceptibility to H5N1 infection and disease in ferrets"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6375-901X","authenticated-orcid":true,"given":"Katherine H.","family":"Restori","sequence":"first","affiliation":[{"name":"Department of Veterinary and Biomedical Science, Pennsylvania State University, University Park, PA 16802, USA."},{"name":"Emory Center of Excellence of Influenza Research and Response 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