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.
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The emergence and molecular evolution of H5N1 influenza viruses in United States dairy cattle
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Dispersal, adaptation and persistence of H5N1 in the sub-Antarctic and Antarctica
High pathogenicity avian influenza virus (HPAIV) H5N1 reached the sub-Antarctic and Antarctica in 2023, subsequently spreading to remote locations within this region where it had devastating impacts on seal, penguin and albatross populations. The threat to marine wildlife over this broad area exemplifies the need to understand H5N1 long-distance dispersal and evolution. We obtained 104 novel viral genomic sequences from samples that we collected at South Georgia, Kerguelen, Crozet, Prince Edward, Falklands/Malvinas Islands and the Antarctic Peninsula in a region spanning 8,000 kilometers. Using recent phylogeographic modeling advances we show that H5N1 spread encompassed numerous transmission events between distant locations, accumulating mammalian-adaptive mutations in the process. Seals are the most affected species, but we reveal that the long-distance eastward virus dispersal better aligns with the long-distance movements of large petrels and albatrosses. The risk of H5N1 endemisation, dispersal to other locations and ongoing evolution are highly concerning.
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CEIRR Risk Assessment Pipeline executive reports on H5N1 highly pathogenic avian influenza 2.3.4.4b, swine H1 1B.2, and H9N2 low pathogenicity avian influenza B4.7.2
The Centers of Excellence for Influenza Research and Response (CEIRR) Risk Assessment Pipeline (RAP) integrates surveillance, phenotypic analysis, and computational modeling across six CEIRR centers to evaluate the pandemic potential of influenza A viruses. By generating coordinated data sets from wild and domestic animals and linking them to viral evolution and functional traits, CEIRR RAP supports the Centers for Disease Control and Prevention’s and the World Health Organization’s risk-assessment efforts. The RAP’s data packages thereby enable evidence-based prioritization of global influenza preparedness and response strategies.
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Can H5N1 avian influenza in dairy cattle be contained in the US?
The emergence and sustained spread of H5N1 in US dairy cattle since 2024 have demonstrated that highly pathogenic avian influenza (HPAI) is capable of establishing long-term transmission in livestock. Genomic surveillance has clarified national patterns of spatial diffusion, interspecies transmission, and viral evolution, but critical data gaps remain that impede efforts to track virus movements in real time, identify modes of transmission, and inform control efforts.
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Highly pathogenic avian influenza (HPAI H5N1, clade 2.3.4.4b, genotype C2.1) in commercial ring-necked pheasants during the 2022 outbreak in the United States
Highly pathogenic avian influenza (HPAI) virus H5N1 clade 2.3.4.4b was introduced into North America in 2021. In 2022, clade 2.3.4.4b spilled into domestic poultry in the United States (U.S.), resulting in the largest HPAI outbreak in U.S. history. In December 2023, H5N1 2.3.4.4b was detected on an upland game bird farm in Pennsylvania. History, clinical signs, and gross lesions were suggestive of marble spleen disease. However, HPAI was identified by real-time reverse-transcriptase polymerase chain reaction; gene sequencing confirmed genotype C2.1 with phylodynamic analyses providing evidence of a wild bird introduction. Predictive mathematical modeling estimated the time of virus introduction onto the farm (15 days (95% C.I., 11-23) before the date of confirmed detection) being similar or longer than previously described for domestic poultry. Although bioexclusion measures were unable to prevent the initial exposure due to industry rearing practices, biocontainment procedures appeared to prevent spread. The lessons learned from this case may be important for other animal agriculture commodities, especially those species that are infrequently handled or observed and may have inaccurately calculated mortality levels. This well-characterized outbreak and other experiences with natural infection should be taken as opportunities to better understand the field dynamics of this virus.
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Emergence of D1.1 reassortant H5N1 avian influenza viruses in North America
Since 2021, highly pathogenic avian influenza viruses (HPAIVs) belonging to H5N1 clade 2.3.4.4b have circulated widely in North American wild birds and repeatedly spilled over into mammals. In 2025, the first H5N1-associated deaths in humans were recorded in the Western hemisphere, raising questions about how the ongoing evolution of the virus in wild birds impacts spillover risk. Here, our analysis of 21,471 H5N1 genomes identified an evolutionary shift in mid-2024, driven by interhemispheric migration from Asia and reassortment with new antigens. The genotypes that dominated the early years of North America’s H5N1 epizootic traced their ancestry back to Europe, but Asia was the source of new “D1.1” genotype viruses that (a) spread faster, (b) have higher reassortment potential, (c) a broader host range, (d) repeatedly spill over to bovines, and (e) cause severe disease in humans, including non-farm workers.
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Can Anything Stop Bird Flu?
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Enhancing the response to avian influenza in the US and globally
The recent emergence of highly pathogenic H5N1 avian influenza virus infections in dairy cows and humans in the U.S. has raised alarms regarding the potential for a pandemic. Over 995 dairy cow herds and at least 70 humans have been affected, including cases of severe disease and the first reported H5N1-related death in the U.S. Sporadic human infections with no known contact with infected animals highlight the possibility of viral adaptation for efficient human-to-human transmission. Concurrently, the virus continues to circulate in wild birds, backyard flocks, and hunted migratory species, further amplifying the risk to humans and domestic animals. This article provides an overview of the current outbreak status, emphasizes the importance of robust surveillance systems to detect emerging strains with pandemic potential, and highlights risks to the U.S. dairy and poultry industries. Recommendations for risk mitigation include enhanced biosecurity measures, improved surveillance, decentralized testing, and targeted public health messaging. The Global Virus Network calls for urgent, proactive measures to prevent widespread outbreaks, leveraging lessons learned from prior pandemics. These measures include targeted vaccination, improved communication strategies to combat vaccine hesitancy, and the incorporation of social sciences to address barriers to public health interventions.
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Pandemic risk stemming from the bovine H5N1 outbreak: an account of the knowns and unknowns
H5N1 subtype influenza A viruses represent a long-standing pandemic concern. 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.
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Controlling bird flu is urgent-for dairy, wildlife, poultry, pets, and people
Highly pathogenic avian influenza viruses of the H5N1 subtype have recently undergone a major geographic expansion. At the same time, these viruses have substantially broadened their host range. Typically, H5N1 circulates in poultry, waterfowl, and shorebirds, but the breadth of avian species affected has increased and spillover to mammals has become common. The recent changes in H5N1 ecology have brought die-offs in wild birds and marine mammals, a sustained outbreak in US dairy cattle, and recurring spillover into domestic cats. Maintenance of H5N1 in wild birds in North America has furthermore produced a persistent risk to US poultry. Circulation of H5N1 in domestic animals has resulted in human infections, especially among farm workers and veterinarians, events that heighten the potential for a pandemic. Through their central position in One Health, veterinarians have a critical role to play in mitigating the impact of H5N1 on animal health, agriculture, and public health.