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Human seasonal H3 IAVs were introduced from human-to-swine in the 1990s in the United States and classified as 1990.1 and 1990.4 lineages; the 1990.4 lineage diversified into 1990.4.A\u2013F clades. Additional introductions occurred in the 2010s, establishing the 2010.1 and 2010.2 lineages. Human zoonotic cases with swine IAV, known as variant viruses, have occurred from the 1990.4 and 2010.1 lineages, highlighting a public health concern. If a variant virus is antigenically drifted from current human seasonal vaccine (HuVac) strains, it may be chosen as a candidate virus vaccine (CVV) for pandemic preparedness purposes. We assessed the zoonotic risk of US swine H3N2 strains by performing phylogenetic analyses of recent swine H3 strains to identify the major contemporary circulating genetic clades. Representatives were tested in hemagglutination inhibition assays with ferret post-infection antisera raised against existing CVVs or HuVac viruses. The 1990.1, 1990.4.A, and 1990.4.B.2 clade viruses displayed significant loss in cross-reactivity to CVV and HuVac antisera, and interspecies transmission potential was subsequently investigated in a pig-to-ferret transmission study. Strains from the three lineages were transmitted from pigs to ferrets via respiratory droplets, but there were differential shedding profiles. These data suggest that existing CVVs may offer limited protection against swine H3N2 infection, and that contemporary 1990.4.A viruses represent a specific concern given their widespread circulation among swine in the United States and association with multiple zoonotic cases.<\/jats:p>","DOI":"10.3390\/v15020331","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:53:18Z","timestamp":1674618798000},"page":"331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Swine-to-Ferret Transmission of Antigenically Drifted Contemporary Swine H3N2 Influenza A Virus Is an Indicator of Zoonotic Risk to Humans"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3082-0398","authenticated-orcid":false,"given":"Carine K.","family":"Souza","sequence":"first","affiliation":[{"name":"Virus and Prion Research Unit, National Animal Disease Center, United States Department of Agriculture-Agricultural Research Service, Ames, IA 50010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1245-1530","authenticated-orcid":false,"given":"J. Brian","family":"Kimble","sequence":"additional","affiliation":[{"name":"Virus and Prion Research Unit, National Animal Disease Center, United States Department of Agriculture-Agricultural Research Service, Ames, IA 50010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tavis K.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Virus and Prion Research Unit, National Animal Disease Center, United States Department of Agriculture-Agricultural Research Service, Ames, IA 50010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zebulun W.","family":"Arendsee","sequence":"additional","affiliation":[{"name":"Virus and Prion Research Unit, National Animal Disease Center, United States Department of Agriculture-Agricultural Research Service, Ames, IA 50010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6221-2493","authenticated-orcid":false,"given":"David E.","family":"Hufnagel","sequence":"additional","affiliation":[{"name":"Virus and Prion Research Unit, National Animal Disease Center, United States Department of Agriculture-Agricultural Research Service, Ames, IA 50010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine M.","family":"Young","sequence":"additional","affiliation":[{"name":"Virus and Prion Research Unit, National Animal Disease Center, United States Department of Agriculture-Agricultural Research Service, Ames, IA 50010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2540-8769","authenticated-orcid":false,"given":"Phillip C.","family":"Gauger","sequence":"additional","affiliation":[{"name":"Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola S.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Pathology and Population Sciences, Royal Veterinary College, University of London, Hertfordshire, London NW1 0TU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Todd","family":"Davis","sequence":"additional","affiliation":[{"name":"Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0234-5403","authenticated-orcid":false,"given":"Sharmi","family":"Thor","sequence":"additional","affiliation":[{"name":"Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4953-7285","authenticated-orcid":false,"given":"Amy L.","family":"Vincent Baker","sequence":"additional","affiliation":[{"name":"Virus and Prion Research Unit, National Animal Disease Center, United States Department of Agriculture-Agricultural Research Service, Ames, IA 50010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"ref_1","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. 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