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Although the United States has stockpiled and is prepared to produce millions of vaccine doses to address an H5N1 pandemic, currently circulating H5N1 viruses contain multiple mutations within the immunodominant head domain of hemagglutinin (HA) compared to the antigens used in stockpiled vaccines. It is unclear if these stockpiled vaccines will need to be updated to match the contemporary H5N1 strains. Here we show that a replicating RNA vaccine expressing the HA of an H5N1 isolated from a US dairy cow confers complete protection against homologous lethal challenge in mice. A repRNA encoding the HA of a clade 1 H5 from 2004 (A\/Vietnam\/1203\/2004) as utilized by some stockpiled vaccines, confers only partial protection. Our data highlight the utility of nucleic acid vaccines to be rapidly updated to match emergent viruses of concern while demonstrating that contemporary bovine H5N1 viruses can evade immunity elicited by historical HA antigens.<\/jats:p>","DOI":"10.1038\/s41467-024-55546-7","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T08:13:39Z","timestamp":1736842419000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Clade 2.3.4.4b but not historical clade 1 HA replicating RNA vaccine protects against bovine H5N1 challenge in mice"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8233-8176","authenticated-orcid":false,"given":"David W.","family":"Hawman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3845-1942","authenticated-orcid":false,"given":"Thomas","family":"Tipih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1606-5821","authenticated-orcid":false,"given":"Eddie","family":"Hodge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Taylor","family":"Stone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2307-5529","authenticated-orcid":false,"given":"Nikole","family":"Warner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Granger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Meade-White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanna","family":"Leventhal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiara","family":"Hatzakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8954-9265","authenticated-orcid":false,"given":"Stephanie","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Gaffney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8101-4348","authenticated-orcid":false,"given":"Kyle","family":"Rosenke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1612-2697","authenticated-orcid":false,"given":"Jesse H.","family":"Erasmus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9448-8227","authenticated-orcid":false,"given":"Heinz","family":"Feldmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,14]]},"reference":[{"key":"55546_CR1","unstructured":"Polansek, T. Bird flu detected in three California dairy herds, state says. https:\/\/www.msn.com\/en-us\/health\/other\/bird-flu-detected-in-three-california-dairy-herds-state-says\/ar-AA1pJT39?ocid=BingNewsSerp (2024)."},{"key":"55546_CR2","unstructured":"APHIS, U. Detections of highly pathogenic avian influenza. https:\/\/www.aphis.usda.gov\/livestock-poultry-disease\/avian\/avian-influenza\/hpai-detections (2024)."},{"key":"55546_CR3","unstructured":"CDC. H5 Bird flu: current situation. https:\/\/www.cdc.gov\/bird-flu\/situation-summary\/index.html (2024)."},{"key":"55546_CR4","unstructured":"State reports single, possible case of bird flu virus in child with mild symptoms. https:\/\/www.cdph.ca.gov\/Programs\/OPA\/Pages\/NR24-037.aspx. (California Department of Public Health, 2024)"},{"key":"55546_CR5","unstructured":"CDC. Technical report: June 2024 highly pathogenic avian influenza A(H5N1) viruses. https:\/\/www.cdc.gov\/bird-flu\/php\/technical-report\/h5n1-06052024.html (2024)."},{"key":"55546_CR6","unstructured":"FDA. Influenza Virus Vaccine, H5N1 (for National Stockpile). https:\/\/www.fda.gov\/vaccines-blood-biologics\/safety-availability-biologics\/influenza-virus-vaccine-h5n1-national-stockpile (US Food and Drug Administration, 2018)."},{"key":"55546_CR7","unstructured":"Seqirus, C. CSL Seqirus, a proud champion of pandemic preparedness, announces U.S. government award in response to avian influenza. https:\/\/www.cslseqirus.us\/news\/csl-seqirus-announces-us-government-award-in-response-to-avian-influenza (2024)."},{"key":"55546_CR8","unstructured":"GSK. 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Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc. Natl. Acad. Sci. USA 111, 13133\u201313138 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"55546_CR12","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1016\/j.ymthe.2018.07.010","volume":"26","author":"JH Erasmus","year":"2018","unstructured":"Erasmus, J. H. et al. A nanostructured lipid carrier for delivery of a replicating viral RNA provides single, low-dose protection against Zika. Mol. Ther. 26, 2507\u20132522 (2018).","journal-title":"Mol. Ther."},{"key":"55546_CR13","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1038\/s41591-024-02955-2","volume":"30","author":"A Saraf","year":"2024","unstructured":"Saraf, A. et al. An Omicron-specific, self-amplifying mRNA booster vaccine for COVID-19: a phase 2\/3 randomized trial. Nat. Med. 30, 1363\u20131372 (2024).","journal-title":"Nat. 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Antibodies against H10N8 avian influenza virus among animal workers in Guangdong Province before November 30, 2013, when the first human H10N8 case was recognized. BMC Med. 12, 205 (2014).","journal-title":"BMC Med."},{"key":"55546_CR25","doi-asserted-by":"publisher","first-page":"2965","DOI":"10.1017\/S0950268815000394","volume":"143","author":"SY Huang","year":"2015","unstructured":"Huang, S. Y. et al. Serological comparison of antibodies to avian influenza viruses, subtypes H5N2, H6N1, H7N3 and H7N9 between poultry workers and non-poultry workers in Taiwan in 2012. Epidemiol. Infect. 143, 2965\u20132974 (2015).","journal-title":"Epidemiol. Infect."},{"key":"55546_CR26","doi-asserted-by":"publisher","first-page":"501","DOI":"10.15585\/mmwr.mm7321e1","volume":"73","author":"S Garg","year":"2024","unstructured":"Garg, S. et al. Outbreak of highly pathogenic avian influenza A(H5N1) viruses in U.S. dairy cattle and detection of two human cases\u2014United States, 2024. MMWR Morb. 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A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation. Mol. Ther. 31, 2360\u20132375 (2023).","journal-title":"Mol. Ther."},{"key":"55546_CR34","doi-asserted-by":"publisher","first-page":"e333","DOI":"10.1097\/INF.0000000000003247","volume":"40","author":"JH Kim","year":"2021","unstructured":"Kim, J. H. et al. Immunogenicity and safety of AS03-adjuvanted H5N1 influenza vaccine in children 6-35 months of age: results from a phase 2, randomized, observer-blind, multicenter, dose-ranging study. Pediatr. Infect. Dis. J. 40, e333\u2013e339 (2021).","journal-title":"Pediatr. Infect. Dis. J."},{"key":"55546_CR35","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abc9396","volume":"12","author":"JH Erasmus","year":"2020","unstructured":"Erasmus, J. H. et al. An alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates. Sci. Transl. Med. 12, eabc9396 (2020).","journal-title":"Sci. Transl. 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J.H.E. is an inventor on patents (US Patent nos. 11,458,209; 11,433,142; 11,752,218; 11,648,321; and 11,654,200) and patent applications (PCT\/US22\/76787, PCT\/US23\/60225, and PCT\/US2024\/010326) pertaining to the LION formulation and repRNA compositions described in the studies. Funders had no role in study design, data interpretation or decision to publish. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"655"}}