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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Can H5N1 avian influenza in dairy cattle be contained in the US?
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The global H5N1 influenza panzootic in mammals
Influenza A viruses have caused more documented global pandemics in human history than any other pathogen1,2. High pathogenicity avian influenza viruses belonging to the H5N1 subtype are a leading pandemic risk. Two decades after H5N1 ‘bird flu’ became established in poultry in Southeast Asia, its descendants have resurged3, setting off a H5N1 panzootic in wild birds that is fuelled by: (1) rapid intercontinental spread, reaching South America and Antarctica for the first time4,5; (2) fast evolution via genomic reassortment6; and (3) frequent spillover into terrestrial7,8 and marine mammals9. The virus has sustained mammal-to-mammal transmission in multiple settings, including European fur farms10,11, South American marine mammals12-15 and US dairy cattle16-19, raising questions about whether humans are next. Historically, swine are considered optimal intermediary hosts that help avian influenza viruses adapt to mammals before jumping to humans20. However, the altered ecology of H5N1 has opened the door to new evolutionary pathways. Dairy cattle, farmed mink or South American sea lions may have the potential to serve as new mammalian gateways for transmission of avian influenza viruses to humans. In this Perspective, we explore the molecular and ecological factors driving the sudden expansion in H5N1 host range and assess the likelihood of different zoonotic pathways leading to an H5N1 pandemic.
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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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When Pigs Fly: Pandemic influenza enters the 21st century
Influenza A viruses (IAVs) are one of the most intensively studied pathogens, due to the severe global mortality and economic disruption associated with influenza pandemics [1]. In addition to annual epidemics, pandemics sporadically occur when a novel IAV host jumps to humans from an animal reservoir [2]. Wild waterfowl have long been considered the most important reservoir host and pandemic risk, but there are indications that mammals are emerging as key reservoirs. Here, we describe how the modernization of swine production during the last half century provided new opportunities for IAVs to become established in swine globally [3–5], resulting in the first influenza pandemic of swine origin in 2009 [6]. A key lesson is that the landscape of pandemic risk is not static but continuously shifting in response to demographic changes in host populations. It is therefore vital to track how transformations in the economy and global trade impact animal contact rates, disease dynamics, and pandemic risk among livestock and companion animals.
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Beyond clinical trials: Evolutionary and epidemiological considerations for development of a universal influenza vaccine
The prospect of universal influenza vaccines is generating much interest and research at the intersection of immunology, epidemiology, and viral evolution. While the current focus is on developing a vaccine that elicits a broadly cross-reactive immune response in clinical trials, there are important downstream questions about global deployment of a universal influenza vaccine that should be explored to minimize unintended consequences and maximize benefits. Here, we review and synthesize the questions most relevant to predicting the population benefits of universal influenza vaccines and discuss how existing information could be mined to begin to address these questions. We review three research topics where computational modeling could bring valuable evidence: immune imprinting, viral evolution, and transmission. We address the positive and negative consequences of imprinting, in which early childhood exposure to influenza shapes and limits immune responses to future infections via memory of conserved influenza antigens. However, the mechanisms at play, their effectiveness, breadth of protection, and the ability to “reprogram” already imprinted individuals, remains heavily debated. We describe instances of rapid influenza evolution that illustrate the plasticity of the influenza virus in the face of drug pressure and discuss how novel vaccines could introduce new selective pressures on the evolution of the virus. We examine the possible unintended consequences of broadly protective (but infection-permissive) vaccines on the dynamics of epidemic and pandemic influenza, compared to conventional vaccines that have been shown to provide herd immunity benefits. In conclusion, computational modeling offers a valuable tool to anticipate the benefits of ambitious universal influenza vaccine programs, while balancing the risks from endemic influenza strains and unpredictable pandemic viruses. Moving forward, it will be important to mine the vast amount of data generated in clinical studies of universal influenza vaccines to ensure that the benefits and consequences of these vaccine programs have been carefully modeled and explored.
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Fogarty International Center collaborative networks in infectious disease modeling: Lessons learnt in research and capacity building
Due to a combination of ecological, political, and demographic factors, the emergence of novel pathogens has been increasingly observed in animals and humans in recent decades. Enhancing global capacity to study and interpret infectious disease surveillance data, and to develop data-driven computational models to guide policy, represents one of the most cost-effective, and yet overlooked, ways to prepare for the next pandemic. Epidemiological and behavioral data from recent pandemics and historic scourges have provided rich opportunities for validation of computational models, while new sequencing technologies and the ‘big data’ revolution present new tools for studying the epidemiology of outbreaks in real time. For the past two decades, the Division of International Epidemiology and Population Studies (DIEPS) of the NIH Fogarty International Center has spearheaded two synergistic programs to better understand and devise control strategies for global infectious disease threats. The Multinational Influenza Seasonal Mortality Study (MISMS) has strengthened global capacity to study the epidemiology and evolutionary dynamics of influenza viruses in 80 countries by organizing international research activities and training workshops. The Research and Policy in Infectious Disease Dynamics (RAPIDD) program and its precursor activities has established a network of global experts in infectious disease modeling operating at the research-policy interface, with collaborators in 78 countries. These activities have provided evidence-based recommendations for disease control, including during large-scale outbreaks of pandemic influenza, Ebola and Zika virus. Together, these programs have coordinated international collaborative networks to advance the study of emerging disease threats and the field of computational epidemic modeling. A global community of researchers and policy-makers have used the tools and trainings developed by these programs to interpret infectious disease patterns in their countries, understand modeling concepts, and inform control policies. Here we reflect on the scientific achievements and lessons learnt from these programs (h-index = 106 for RAPIDD and 79 for MISMS), including the identification of outstanding researchers and fellows; funding flexibility for timely research workshops and working groups (particularly relative to more traditional investigator-based grant programs); emphasis on group activities such as large-scale modeling reviews, model comparisons, forecasting challenges and special journal issues; strong quality control with a light touch on outputs; and prominence of training, data-sharing, and joint publications.
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Origins of the 1918 Pandemic: Revisiting the Swine “Mixing Vessel” Hypothesis
How influenza A viruses host-jump from animal reservoir species to humans, which can initiate global pandemics, is a central question in pathogen evolution. The zoonotic and spatial origins of the influenza virus associated with the “Spanish flu” pandemic of 1918 have been debated for decades. Outbreaks of respiratory disease in US swine occurred concurrently with disease in humans, raising the possibility that the 1918 virus originated in pigs. Swine also were proposed as “mixing vessel” intermediary hosts between birds and humans during the 1957 Asian and 1968 Hong Kong pandemics. Swine have presented an attractive explanation for how avian viruses overcome the substantial evolutionary barriers presented by different cellular environments in humans and birds. However, key assumptions underpinning the swine mixing-vessel model of pandemic emergence have been challenged in light of new evidence. Increased surveillance in swine has revealed that human-to-swine transmission actually occurs far more frequently than the reverse, and there is no empirical evidence that swine played a role in the emergence of human influenza in 1918, 1957, or 1968. Swine-to-human transmission occurs periodically and can trigger pandemics, as in 2009. But swine are not necessary to mediate the establishment of avian viruses in humans, which invites new perspectives on the evolutionary processes underlying pandemic emergence.
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Reassortment in segmented RNA viruses: mechanisms and outcomes
Segmented RNA viruses are widespread in nature and include important human, animal and plant pathogens, such as influenza viruses and rotaviruses. Although the origin of RNA virus genome segmentation remains elusive, a major consequence of this genome structure is the capacity for reassortment to occur during co-infection, whereby segments are exchanged among different viral strains. Therefore, reassortment can create viral progeny that contain genes that are derived from more than one parent, potentially conferring important fitness advantages or disadvantages to the progeny virus. However, for segmented RNA viruses that package their multiple genome segments into a single virion particle, reassortment also requires genetic compatibility between parental strains, which occurs in the form of conserved packaging signals, and the maintenance of RNA and protein interactions. In this Review, we discuss recent studies that examined the mechanisms and outcomes of reassortment for three well-studied viral families – Cystoviridae, Orthomyxoviridae and Reoviridae – and discuss how these findings provide new perspectives on the replication and evolution of segmented RNA viruses.
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Reverse zoonosis of influenza to swine: new perspectives on the human-animal interface
The origins of the 2009 influenza A (H1N1) pandemic in swine are unknown, highlighting gaps in our understanding of influenza A virus (IAV) ecology and evolution. We review how recently strengthened influenza virus surveillance in pigs has revealed that influenza virus transmission from humans to swine is far more frequent than swine-to-human zoonosis, and is central in seeding swine globally with new viral diversity. The scale of global human-to-swine transmission represents the largest ‘reverse zoonosis’ of a pathogen documented to date. Overcoming the bias towards perceiving swine as sources of human viruses, rather than recipients, is key to understanding how the bidirectional nature of the human-animal interface produces influenza threats to both hosts.