The Emergence and Rapid Spread of HPAI A(H5N1) D1.1 in North America: Genetic Insights and Public Health Risks

In late 2021, Eurasian Highly Pathogenic Avian Influenza (HPAI) A(H5N1) clade 2.3.4.4b viruses were introduced to North America, rapidly reassorting with local low-pathogenic strains to generate diverse genotypes. In September 2024, we detected novel reassortant viruses assigned to an emergent genotype designated D1.1. Using an extensive North American surveillance network, we tracked the rapid spread of genotype D1.1 viruses during the autumn 2024 migration of wild birds. D1.1 viruses quickly expanded generally southeastward across North America from Alaska and British Columbia to Georgia, becoming the dominant HPAI A(H5N1) genotype across the Pacific, Central, and Mississippi flyways. Phylogenetic analyses reveal localized diversification of viruses within the clade, highlighting adaptive capacity. The rapid dissemination of D1.1 viruses among wild birds coincided with spillover to other hosts, including humans and dairy cattle. Genetic and antigenic characterization of D1.1 viruses identified key mutations that may enhance viral fitness and transmissibility including an E627K mutation in the PB2 protein of a virus from a bobcat which has been associated with mammalian adaptation. Importantly, this mutation was not found in wild bird isolates. Given rapid widespread dissemination of D1.1 viruses across the continent, the adaptive capacity exhibited, and severe clinical outcomes in two recent human spillover events, findings of this study attest to the importance of interjurisdictional viral surveillance for understanding trends in evolution and adaptation. Continued monitoring of the evolution of HPAI A(H5N1) D1.1 may prove useful towards informing domestic animal and human health strategies and mitigating further spillover events.

Walter N. Harringtona, Ahmed Kandeila, Andrew M. Rameyb, Anthony Signorec, Beate Crossleyd, Bradley S. Cohene, Christina A. Ahlstromb, Cory J. Highwaye, Daniel Rejmanekd, David Stallknechtf, Deborah Carterf, Evan J. Buckb, Jamie C. FeddersenG, Jacqueline M. NoltingH, John Franksa, Julianna LenochI, Karlie Woodarda, Lauren SmithH, Laura C. Scottb, Lance Millera, Lisa Kerchera, Lydia P. Holmese, Madison OwsianyH, Mia TorchettiJ, Mohammad Jahid JawadH, Nathan J. Steelmane, Nicole Nemethf, Paul LinkK, Rebecca Poulsonf, Richard J. Webbya, Sarah BevinsI, Tom Fabrizioa, Trushar Jeevana, Yohannes Berhanec aDepartment of Host-Microbe Interactions, St. Jude Children’s Research Hospital bAlaska Science Center, United States Geological Survey (USGS) cNational Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, Canada dSchool of Veterinary Medicine, University of California, Davis eDepartment of Biology, Tennessee Technological University fSoutheastern Cooperative Wildlife Disease Study, University of Georgia GMigratory Gamebird Program, Tennessee Wildlife Resources Agency, Nashville, Tennessee, USA HDepartment of Veterinary Preventive Medicine, The Ohio State University IWildlife Services, National Wildlife Disease Program, U.S. Department of Agriculture, APHIS JNational Veterinary Services Laboratories, U.S. Department of Agriculture KLouisiana Department of Wildlife and Fisheries

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