{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:49:33Z","timestamp":1793371773890,"version":"4.5.0"},"reference-count":43,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"819","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,10,8]]},"abstract":"<jats:p>In early 2024, clade 2.3.4.4b highly pathogenic avian influenza (HPAI) A H5N1 virus was detected in United States dairy cattle. Although so far the public health threat of contemporary clade 2.3.4.4b H5N1 virus strains remains low, continued circulation in mammals and frequent spillover into humans poses a threat of pandemic H5N1. The United States and other countries have stockpiled vaccines and have plans in place to rapidly produce additional vaccine doses should a pandemic H5N1 virus emerge. However, the continued antigenic drift of clade 2.3.4.4b H5N1 antigens compared with historical antigens used by stockpiled vaccines has raised questions of whether these vaccines will confer protection or whether stockpiles need to be updated. We recently evaluated a replicating RNA (repRNA) vaccine against lethal contemporary 2.3.4.4b H5N1 virus challenge in mice and found that a homologous, but not historical, H5 hemagglutinin (HA)\u2013based vaccine conferred protection. Here, we further evaluated the protective capacity of a repRNA expressing the contemporary 2.3.4.4b HA or a repRNA expressing a historical H5 HA (A\/Vietnam\/1203\/2004) in a recently developed lethal nonhuman primate (NHP) challenge model. We found that both vaccines conferred robust protection against lethal 2.3.4.4b H5N1 virus challenge, reducing viral loads and signs of respiratory illness. Our data show that the repRNA platform can elicit protective immunity against lethal influenza virus challenge in NHPs and that historical H5 HAs can elicit cross-protective immunity.<\/jats:p>","DOI":"10.1126\/scitranslmed.adw4646","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T17:59:46Z","timestamp":1759946386000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["A replicating RNA vaccine protects cynomolgus macaques against lethal clade 2.3.4.4b influenza A H5N1 virus challenge"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8233-8176","authenticated-orcid":true,"given":"David W.","family":"Hawman","sequence":"first","affiliation":[{"name":"HDT Bio, Seattle, WA 98109, USA."},{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Griffin","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7779-3059","authenticated-orcid":true,"given":"Atsushi","family":"Okumura","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanna S.","family":"Leventhal","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahati","family":"Agumamidi","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Michael","family":"Chorabik","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Altynova","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6657-7588","authenticated-orcid":true,"given":"Matthew","family":"Lewis","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4833-0255","authenticated-orcid":true,"given":"Troy","family":"Hinkley","sequence":"additional","affiliation":[{"name":"HDT Bio, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6742-1270","authenticated-orcid":true,"given":"E. Taylor","family":"Stone","sequence":"additional","affiliation":[{"name":"HDT Bio, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2307-5529","authenticated-orcid":true,"given":"Nikole","family":"Warner","sequence":"additional","affiliation":[{"name":"HDT Bio, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8954-9265","authenticated-orcid":true,"given":"Stephanie","family":"Park","sequence":"additional","affiliation":[{"name":"HDT Bio, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7567-446X","authenticated-orcid":true,"given":"Jamie","family":"Lovaglio","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7091-3046","authenticated-orcid":true,"given":"Brian J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2300-1818","authenticated-orcid":true,"given":"Patrick","family":"Hanley","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0803-6177","authenticated-orcid":true,"given":"Greg","family":"Saturday","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8907-8821","authenticated-orcid":true,"given":"Carl","family":"Shaia","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5354-9270","authenticated-orcid":true,"given":"Chad","family":"Clancy","sequence":"additional","affiliation":[{"name":"Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8101-4348","authenticated-orcid":true,"given":"Kyle","family":"Rosenke","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1612-2697","authenticated-orcid":true,"given":"Jesse H.","family":"Erasmus","sequence":"additional","affiliation":[{"name":"HDT Bio, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9448-8227","authenticated-orcid":true,"given":"Heinz","family":"Feldmann","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","unstructured":"CDC \u201cH5 bird flu: Current situation\u201d (2025); https:\/\/www.cdc.gov\/bird-flu\/situation-summary\/index.html."},{"key":"e_1_3_2_3_2","unstructured":"Public Health Agency of Canada \u201cStatement from the Public Health Agency of Canada: Update on avian influenza and risk to Canadians \u201d 13 November 2024; https:\/\/www.canada.ca\/en\/public-health\/news\/2024\/11\/update-on-avian-influenza-and-risk-to-canadians.html."},{"key":"e_1_3_2_4_2","unstructured":"M. Stobbe \u201cA Canadian teen is in critical condition with what is believed to be bird flu \u201d AP News 12 November 2024; https:\/\/apnews.com\/article\/bird-flu-canada-teen-hospitalized-45d7c944883fb17aeb37e96e679cc53e."},{"key":"e_1_3_2_5_2","unstructured":"M. Stobbe J. Aleccia \u201cBird flu: Louisiana patient is first severe case and California declares emergency \u201d AP News 18 December 2024; https:\/\/apnews.com\/article\/bird-flu-severe-louisiana-2b4a5f55a05cf8be9b169c15e8b9582d."},{"key":"e_1_3_2_6_2","unstructured":"L. Schnirring \u201cMexico\u2019s fatal H5N1 case involved D1.1 genotype which has been tied to serious illness \u201d Center for Infectious Disease Research & Policy University of Minnesota 17 April 2025; https:\/\/www.cidrap.umn.edu\/avian-influenza-bird-flu\/mexicos-fatal-h5n1-case-involved-d11-genotype-which-has-been-tied-serious."},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adt0180"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid3007.240689"},{"key":"e_1_3_2_9_2","unstructured":"FDA Influenza Virus Vaccine H5N1 (for National Stockpile) (2018); https:\/\/www.fda.gov\/vaccines-blood-biologics\/vaccines\/influenza-virus-vaccine-h5n1-national-stockpile."},{"key":"e_1_3_2_10_2","unstructured":"GSK \u201cH5N1 vaccine approved by the U.S. FDA as pandemic influenza preparedness measure \u201d 25 November 2013; https:\/\/www.gsk.com\/en-gb\/media\/press-releases\/h5n1-vaccine-approved-by-the-us-fda-as-pandemic-influenza-preparedness-measure\/."},{"key":"e_1_3_2_11_2","unstructured":"CSL Seqirus \u201cCSL Seqirus a proud champion of pandemic preparedness announces U.S. government award in response to avian influenza \u201d 30 May 2024; https:\/\/www.cslseqirus.us\/news\/csl-seqirus-announces-us-government-award-in-response-to-avian-influenza."},{"key":"e_1_3_2_12_2","unstructured":"J. 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Tipih V. Mariappan K. C. Yinda K. Meade-White M. Lewis A. Okumura N. McCarthy C. Clancy E. de Wit V. J. Munster H. U. Feldmann K. Rosenke Recent bovine HPAI H5N1 isolate is highly virulent for mice rapidly causing acute pulmonary and neurologic disease. bioRxiv 2024.08.19.608652 [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.08.19.608652.","DOI":"10.1101\/2024.08.19.608652"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4461"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01021-0"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2116597"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01318-5"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011298"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104196"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.75537"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-01029-1"},{"key":"e_1_3_2_43_2","doi-asserted-by":"crossref","unstructured":"D. Hawman T. Tipih E. Hodge K. Meade-White S. Leventhal K. Hatzakis S. Park K. Gaffney E. T. Stone N. Warner K. Rosenke J. Erasmus H. Feldmann Clade 2.3.4.4b but not historical clade 1 HA replicating RNA vaccine protects against bovine H5N1 challenge. Res. Sq. 10.21203\/rs.3.rs-4946897\/v1 [Preprint] (2024).","DOI":"10.21203\/rs.3.rs-4946897\/v1"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02289823"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adw4646","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T17:59:49Z","timestamp":1759946389000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adw4646"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":43,"journal-issue":{"issue":"819","published-print":{"date-parts":[[2025,10,8]]}},"alternative-id":["10.1126\/scitranslmed.adw4646"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adw4646","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,8]]},"assertion":[{"value":"2025-02-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-20","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadw4646"}}