{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:05:16Z","timestamp":1790809516177,"version":"4.1.0"},"posted":{"date-parts":[[2026,7,22]]},"group-title":"Microbiology","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>In fall of 2025, a fatal infection of highly pathogenic avian influenza (HPAI) virus H5N5 occurred. To define the risk of this emerging virus to humans, we performed a comprehensive analysis based on our established triage. Serological analysis revealed that humans across all birth years had no detectable neutralizing antibodies to this H5N5 isolate. Further characterization revealed a lack of phenotypic signatures associated with epidemiologically successful influenza viruses in humans, including reduced replication in human airway cells and an avian-like pH of inactivation. Additionally, assessment of H5N5 in ferrets revealed a lack of direct contact transmission and moderate disease severity. H5N5 infection in ferrets with prior immunity against the 2009 H1N1 pandemic strain resulted in fewer clinical signs and reduced viral shedding. Together our data suggest that the current H5N5 HPAI lineage poses a low pandemic risk.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>HPAI H5N5 viruses have caused widespread infection and death in avian species, and characterizing their pandemic risk traits is critical to understanding the threat posed to humans. In this work we analyzed an isolate that resulted in a human fatality in 2025. We found that this strain lacks many key features of influenza viruses with epidemiological success in humans including reduced growth in human lung cultures, a pH of inactivation less than 5.0, and lack of transmission to cohoused recipient ferrets. Prior immunity with seasonal H1N1 strain also reduced the viral load and disease burden of the virus. Taken together, these data suggest that currently circulating H5N5 poses a low risk to humans but highlights the importance of phenotypic characterizations for future risk assessments as the virus evolves in wild birds.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.20.739507","type":"posted-content","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T12:40:19Z","timestamp":1784724019000},"source":"Crossref","is-referenced-by-count":1,"title":["A lethal human H5N5 influenza virus isolate exhibits low pandemic risk traits"],"prefix":"10.64898","author":[{"given":"Michelle N.","family":"Vu","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace E.","family":"Quirk","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis E.","family":"Smathers","sequence":"additional","affiliation":[{"name":"Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn","family":"Busfield-Thomason","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaina L.","family":"Dorazio","sequence":"additional","affiliation":[{"name":"Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelyn R.","family":"Domke","sequence":"additional","affiliation":[{"name":"Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. M.","family":"Humber","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Sembrat","sequence":"additional","affiliation":[{"name":"Divison of Pulmonary, Allergy, Critical Care & Sleep Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita K.","family":"McElroy","sequence":"additional","affiliation":[{"name":"Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"name":"Division of Infectious Diseases, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Le Sage","sequence":"additional","affiliation":[{"name":"Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-2150","authenticated-orcid":false,"given":"Seema S.","family":"Lakdawala","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072706301576000_2026.07.20.739507v1.1","doi-asserted-by":"crossref","first-page":"e0042425","DOI":"10.1128\/jvi.00424-25","article-title":"Clade 2.3.4.4b highly pathogenic avian influenza H5N1 viruses: knowns, unknowns, and challenges","volume":"99","year":"2025","journal-title":"J Virol"},{"key":"2026072706301576000_2026.07.20.739507v1.2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02725-12"},{"key":"2026072706301576000_2026.07.20.739507v1.3","doi-asserted-by":"publisher","DOI":"10.3201\/eid1706.101406"},{"key":"2026072706301576000_2026.07.20.739507v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2012.12.025"},{"key":"2026072706301576000_2026.07.20.739507v1.5","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.3390\/v14122725","article-title":"Analysis of avian influenza (H5N5) viruses isolated in the southwestern European part of the Russian Federation in 2020-2021","volume":"14","year":"2022","journal-title":"Viruses"},{"key":"2026072706301576000_2026.07.20.739507v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114479"},{"key":"2026072706301576000_2026.07.20.739507v1.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2518178"},{"key":"2026072706301576000_2026.07.20.739507v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49117-z"},{"key":"2026072706301576000_2026.07.20.739507v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2018.03.005"},{"key":"2026072706301576000_2026.07.20.739507v1.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1524384113"},{"key":"2026072706301576000_2026.07.20.739507v1.11","doi-asserted-by":"crossref","first-page":"e0006624","DOI":"10.1128\/mmbr.00066-24","article-title":"Viral factors underlying the pandemic potential of influenza viruses","volume":"89","year":"2025","journal-title":"Microbiol Mol Biol Rev"},{"key":"2026072706301576000_2026.07.20.739507v1.12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002443"},{"key":"2026072706301576000_2026.07.20.739507v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/nature15379"},{"key":"2026072706301576000_2026.07.20.739507v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.09.008"},{"key":"2026072706301576000_2026.07.20.739507v1.15","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00552-19"},{"key":"2026072706301576000_2026.07.20.739507v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2016.07.007"},{"key":"2026072706301576000_2026.07.20.739507v1.17","doi-asserted-by":"publisher","DOI":"10.3201\/eid3103.241485"},{"key":"2026072706301576000_2026.07.20.739507v1.18","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adw4856"},{"key":"2026072706301576000_2026.07.20.739507v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48475-y"},{"key":"2026072706301576000_2026.07.20.739507v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-026-72941-4"},{"key":"2026072706301576000_2026.07.20.739507v1.21","doi-asserted-by":"crossref","first-page":"e0044526","DOI":"10.1128\/mbio.00445-26","article-title":"Population immunity to clade 2.3.4.4b H5N1 is dominated by anti-neuraminidase antibodies","volume":"17","year":"2026","journal-title":"MBio"},{"key":"2026072706301576000_2026.07.20.739507v1.22","unstructured":"2026. Avian influenza overview March\u2013May 2026. European Centre for Disease Prevention and Control. https:\/\/www.ecdc.europa.eu\/en\/publications-data\/avian-influenza-overview-march-may-2026. Retrieved 15 July 2026."},{"key":"2026072706301576000_2026.07.20.739507v1.23","unstructured":"2023. Detections of Highly Pathogenic Avian Influenza in Wild Birds. Animal and Plant Health Inspection Service. dhodge. https:\/\/www.aphis.usda.gov\/livestock-poultry-disease\/avian\/avian-influenza\/hpai-detections\/wild-birds. Retrieved 15 July 2026."},{"key":"2026072706301576000_2026.07.20.739507v1.24","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a118408"},{"key":"2026072706301576000_2026.07.20.739507v1.25","doi-asserted-by":"crossref","first-page":"xtac007","DOI":"10.1093\/femsmc\/xtac007","article-title":"Secondary infection with Streptococcus pneumoniae decreases influenza virus replication and is linked to severe disease","volume":"3","year":"2022","journal-title":"FEMS Microbes"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.20.739507","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T13:30:23Z","timestamp":1785159023000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.20.739507"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":25,"URL":"https:\/\/doi.org\/10.64898\/2026.07.20.739507","relation":{},"subject":[],"published":{"date-parts":[[2026,7,22]]},"subtype":"preprint"}}