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Owing to their global occurrence in poultry, humans are routinely exposed to these viruses, and hundreds of human cases have been documented worldwide since 2003. The relevant viral lineages are not static, however, and have recently undergone a massive expansion of host range and geographic distribution. Within this expansion, the introduction of H5N1 viruses into dairy cattle in the United States has spawned a novel animal-human interface. In response, public health agencies have sought to evaluate the risk of an H5N1 pandemic stemming from the bovine outbreak. These assessments draw on evidence from the field and the laboratory to score a series of recognized risk factors. As such, their utility hinges on fundamental understanding of the processes that drive pandemic emergence and the availability of relevant data. Advancing this understanding and gathering data prior to and during an outbreak are primary missions of the NIAID Centers of Excellence for Influenza Research and Response (CEIRR) Network. To further these goals and highlight the need for an invigorated response across US agencies, here, we review gaps in understanding of the dairy cattle outbreak and identify constraints on efforts to close these gaps.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.00052-25","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T13:47:07Z","timestamp":1740664027000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":33,"title":["Pandemic risk stemming from the bovine H5N1 outbreak: an account of the knowns and unknowns"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9829-112X","authenticated-orcid":true,"given":"Anice C.","family":"Lowen","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4953-7285","authenticated-orcid":true,"given":"Amy L.","family":"Baker","sequence":"additional","affiliation":[{"name":"Virus and Prion Research Unit, National Animal Disease Center, Agricultural Research Service, U.S. Department of Pathobiology, Agriculture","place":["Ames, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0738-8453","authenticated-orcid":true,"given":"Andrew S.","family":"Bowman","sequence":"additional","affiliation":[{"name":"Department of Veterinary Preventive Medicine, The Ohio State University","place":["Columbus, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6551-1827","authenticated-orcid":true,"given":"Adolfo","family":"Garc\u00eda-Sastre","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]},{"name":"Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]},{"name":"Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]},{"name":"The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]},{"name":"Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]},{"name":"The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2928-7506","authenticated-orcid":true,"given":"Scott E.","family":"Hensley","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Pennsylvania","place":["Philadelphia, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-2150","authenticated-orcid":true,"given":"Seema S.","family":"Lakdawala","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise H.","family":"Moncla","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, The University of Pennsylvania","place":["Philadelphia, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha I.","family":"Nelson","sequence":"additional","affiliation":[{"name":"National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health (NIH)","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3248-1761","authenticated-orcid":true,"given":"Andrew","family":"Pekosz","sequence":"additional","affiliation":[{"name":"W. 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