Abstract
Prior to 2024, highly pathogenic avian influenza H5N1 clade 2.3.4.4b viruses circulated predominantly in wild birds and poultry. In 2024 and 2025, 2.3.4.4b genotypes B3.13 and D1.1 were detected in United States dairy cattle. Using whole-genome and segment-specific phylodynamic inference, we estimate that B3.13 and D1.1 spilled over from wild birds into dairy cattle in late 2023 and late 2024, respectively. Spillover occurred shortly after the formation of the reassortant genotypes and was followed by months of cryptic transmission prior to detection. We found that both B3.13 and D1.1 evolved at higher rates in cattle relative to birds, primarily due to relaxed purifying selection. Site-specific analyses identified genomic sites under positive selection in cattle relative to birds, indicating adaptation and likely contributing to improved viral fitness after spillover. Intensified genomic surveillance in dairy cattle is essential as population immunity introduces additional selection pressures, with ever-changing risk for human emergence.
Competing Interest Statement
M.A.S. receives contracts from Johnson & Johnson and Gilead Sciences outside the scope of this work. M.U.G.K. received consulting fees from Takeda, Bavaria Nordic, and Google DeepMind for work unrelated to the manuscript.
Funder Information Declared
Fonds voor Wetenschappelijk Onderzoek - Vlaanderen, G051322N, G051323N
UK Medical Research Council/Department for Environment, Food and Rural Affairs (DEFRA) FluTrailMap-One Health consortium, MR/Y03368X/1
Biotechnology and Biological Sciences Research Council (BBSRC)/DEFRA ‘FluTrailMap’ consortium, BB/Y007298/1
Pirbright Institute’s Strategic Program Grants, BBS/E/PI/230002A, BBS/E/PI/230002B
EMBO Installation Grant, 5305
Academy of Medical Sciences Springboard, 1049
Centers of Excellence for Influenza Research and Response, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Department of Health and Human Services, 75N93021C00015, 75N93021C00014
National Institutes of Health, AI135995, AI153044, AI192139
Rockefeller Foundation, PC-2022-POP-005
Health AI Programme from Google.org
Oxford Martin School Programmes in Pandemic Genomics & Digital Pandemic Preparedness
European Union's Horizon Europe, 874850, 101086640
Wellcome Trust, 303666/Z/23/Z, 226052/Z/22/Z, 228186/Z/23/Z
United Kingdom Research and Innovation, APP8583
Medical Research Foundation, MRF-RG-ICCH-2022-100069
UK International Development, 301542-403
Bill & Melinda Gates Foundation, INV-063472, INV-090281
Novo Nordisk Foundation, NNF24OC0094346
Source:
Link: https://www.biorxiv.org/content/10.64898/2026.03.30.713641v1
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