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Since their emergence in the 1990s, H5N1 influenza viruses have significantly expanded their geographical range and host species, raising global concern about the potential for sustained human-to-human transmission. In this review, we examine the virological characteristics of currently circulating H5N1 strains, key molecular barriers limiting their spread among humans, and critical areas of future research to mitigate the ongoing H5N1 panzootic and prevent future pandemics.<\/jats:p>","DOI":"10.1093\/immhor\/vlaf062","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T20:43:28Z","timestamp":1765917808000},"source":"Crossref","is-referenced-by-count":0,"title":["Immunological and virological questions for H5N1 pandemic emergence"],"prefix":"10.1093","volume":"9","author":[{"given":"Mario A","family":"Pe\u00f1a-Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine , New Haven, CT,","place":["United States"]},{"name":"Department of Microbial Pathogenesis, Yale University School of Medicine , New Haven, CT,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0310-9047","authenticated-orcid":false,"given":"Miyu","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine , New Haven, CT,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"2026012706070806400_vlaf062-B1","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1038\/s41586-024-08054-z","article-title":"The global H5N1 influenza panzootic in mammals","volume":"637","author":"Peacock","year":"2025","journal-title":"Nature"},{"key":"2026012706070806400_vlaf062-B2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41572-018-0002-y","article-title":"Influenza","volume":"4","author":"Krammer","year":"2018","journal-title":"Nat Rev Dis 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