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Here, we demonstrated that an inactivated, multivalent whole-virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is composed of four \u03b2-propiolactone\u2013inactivated low-pathogenicity avian IAV subtypes of H1N9, H3N8, H5N1, and H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to control animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.<\/jats:p>","DOI":"10.1126\/scitranslmed.abo2167","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T13:56:26Z","timestamp":1657720586000},"source":"Crossref","is-referenced-by-count":32,"title":["An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4506-8127","authenticated-orcid":true,"given":"Jaekeun","family":"Park","sequence":"first","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4111-0057","authenticated-orcid":true,"given":"Sharon L.","family":"Fong Legaspi","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis M.","family":"Schwartzman","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian M.","family":"Gygli","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8637-3614","authenticated-orcid":true,"given":"Lex M.","family":"Matthews","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongli","family":"Xiao","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2134-610X","authenticated-orcid":true,"given":"Mitchell D.","family":"Ramuta","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8743-7189","authenticated-orcid":true,"given":"Luz Angela","family":"Rosas","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6174-5418","authenticated-orcid":true,"given":"Stephanie L.","family":"Williams","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, 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