{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T15:35:08Z","timestamp":1781537708804,"version":"3.54.5"},"reference-count":89,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"837","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["75N93021C00016"],"award-info":[{"award-number":["75N93021C00016"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institutes of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["75N93021C00016"],"award-info":[{"award-number":["75N93021C00016"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,2,18]]},"abstract":"<jats:p>\n                    Highly pathogenic avian influenza A(H5N1) hemagglutinin (HA) clade 2.3.4.4b viruses are now circulating in wild birds and agricultural species (poultry and dairy cows), resulting in multiple human infections. Both preclinical and clinical data for treating A(H5N1) with US Food and Drug Administration\u2013approved anti-influenza drugs are limited. Here, we examined the protection conferred by one, two, or three doses of the newest approved anti-influenza drug, baloxavir, in ferrets lethally challenged with either an avian- or bovine-origin A(H5N1) virus. All dosing regimens improved survival and clinical outcomes with protection ranging from 50 to 100%. Compared with vehicle-only treatment, baloxavir regimens decreased virus shedding, lung pathology, and viremia and eliminated viral spread to the brain. Multidose therapy yielded the best outcomes overall. Single-dose baloxavir prophylaxis with an avian virus challenge resulted in the low-frequency presence of polymerase acidic (PA) protein containing the E23K substitution, whereas all treatment regimens after a bovine-origin virus challenge induced at least one instance of PA containing the I38T substitution. Both PA-E23K and PA-I38T were predicted to decrease potential baloxavir\u2013PA protein interactions, and they phenotypically reduced susceptibility of the virus to baloxavir by 3.8-fold [50% effective concentration (EC\n                    <jats:sub>50<\/jats:sub>\n                    )\u00a0=\u00a015.13\u00a0nanomolar, PA-E23K] and 77.3-fold (EC\n                    <jats:sub>50<\/jats:sub>\n                    \u00a0=\u00a0307.40\u00a0nanomolar, PA-I38T) in polymerase assays. Baloxavir is a single-dose drug for treating seasonal influenza. We show that multidose regimens of baloxavir may be most efficacious against highly pathogenic avian influenza A(H5N1) in a preclinical ferret model, with effective control of both severe disease and neurological involvement.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adt3889","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T18:58:48Z","timestamp":1771441128000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Baloxavir alleviates severe disease and viremia in ferrets infected with avian- or bovine-origin influenza A(H5N1) virus"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9980-2112","authenticated-orcid":true,"given":"Jeremy C.","family":"Jones","sequence":"first","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1757-4532","authenticated-orcid":true,"given":"Konstantin","family":"Andreev","sequence":"additional","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3653-794X","authenticated-orcid":true,"given":"Vyoma","family":"Sheth","sequence":"additional","affiliation":[{"name":"Center of Excellence for Data Driven Discovery, Department of Structural Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8525-3500","authenticated-orcid":true,"given":"Kincaid","family":"Rowbotham","sequence":"additional","affiliation":[{"name":"Center of Excellence for Data Driven Discovery, Department of Structural Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7535-0545","authenticated-orcid":true,"given":"Peter","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Comparative Pathology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3685-4337","authenticated-orcid":true,"given":"Christopher J.","family":"Patton","sequence":"additional","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Seiler","sequence":"additional","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2305-0636","authenticated-orcid":true,"given":"John","family":"Franks","sequence":"additional","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3253-6961","authenticated-orcid":true,"given":"Ahmed","family":"Kandeil","sequence":"additional","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."},{"name":"Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza, 12622, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8497-5571","authenticated-orcid":true,"given":"Lance","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0556-6196","authenticated-orcid":true,"given":"M. Madan","family":"Babu","sequence":"additional","affiliation":[{"name":"Center of Excellence for Data Driven Discovery, Department of Structural Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4397-7132","authenticated-orcid":true,"given":"Richard J.","family":"Webby","sequence":"additional","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9067-5682","authenticated-orcid":true,"given":"Elena A.","family":"Govorkova","sequence":"additional","affiliation":[{"name":"Department of Host\u2013Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN 38120, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-025-01189-4"},{"key":"e_1_3_2_3_2","unstructured":"World Health Organization WHO Manual on Animal Influenza Diagnosis and Surveillance (World Health Organization 2011); https:\/\/iris.who.int\/bitstream\/handle\/10665\/68026\/who_cds?sequence=1."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/tropicalmed4020072"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06631-2"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(24)00438-9"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae379"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2405371"},{"key":"e_1_3_2_9_2","unstructured":"US Centers for Disease Control and Prevention \u201dCDC confirms second human H5 bird flu case in Michigan; Third case tied to dairy outbreak\u201d (3 May 2024); https:\/\/www.cdc.gov\/media\/releases\/2024\/p0530-h5-human-case-michigan.html."},{"key":"e_1_3_2_10_2","unstructured":"US Centers for Disease Control And Prevention \u201cH5 bird flu: Current situation\u201d (8 January 2026); https:\/\/www.cdc.gov\/bird-flu\/situation-summary\/index.html."},{"key":"e_1_3_2_11_2","unstructured":"Washington State Department of Health \u201cGrays Harbor County resident dies from complications of avian influenza\u201d (21 November 2025); https:\/\/doh.wa.gov\/newsroom\/grays-harbor-county-resident-dies-complications-avian-influenza."},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07766-6"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08254-7"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08246-7"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2024.2332667"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2022.105499"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00469-2"},{"issue":"2","key":"e_1_3_2_18_2","first-page":"ii25","article-title":"Oseltamivir in human avian influenza infection","volume":"65","author":"Smith J. R.","year":"2010","unstructured":"J. R. Smith, Oseltamivir in human avian influenza infection. J. Antimicrob. Chemother. 65 (Suppl. 2), ii25\u2013ii33 (2010).","journal-title":"J. Antimicrob. 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