The highly Pathogenic Avian Influenza H5N1 (HPAI H5N1) has a long history, first detected in chickens in Scotland back in 1959. Since then, it has spread globally, primarily aided by migratory birds.
In 1996, a significant turning point occurred when the HPAI H5N1 variant was identified in domestic waterfowl in Southern China. This particular strain, known as A/Goose/Guangdong/1/1996, led to the first documented human infections, resulting in 18 cases, six of which were fatal, in Hong Kong in 1997.
For almost three decades, the virus circulated in diverse evolutionary lineages and clades, significantly affecting avian and mammalian hosts worldwide. Starting in 2013, the HPAI H5Nx viruses from clade 2.3.4.4 began to surf through Southeast Asia, featuring three neuraminidase subtypes: N1, N6, and N8.
The emergence of clade 2.3.4.4b H5N8 in late 2013 marked another shift, as these viruses were detected in China and subsequently South Korea in early 2014. By early 2020, a novel variant of the clade 2.3.4.4b H5N1 virus emerged in Europe and quickly spread across Europe, Asia, and Africa, driven primarily by wild birds.
By late 2020, this novel H5N1 clade 2.3.4.4b variant had become the predominant strain globally, leading to a panzootic in wild birds and significant outbreaks in domestic birds, along with sporadic instances of spillover into mammals.
In December 2021, the virus made its way across the Atlantic, transported by wild birds from Europe to Canada, and soon reached the United States in early 2022. After multiple introduced genotypes, specific Eurasian avian lineages, A1 and A3 began reassorting with low pathogenic avian influenza (LPAI) viruses, culminating in new genotypes, B3.13 and D1.1, that emerged in late 2023 and September 2024, respectively.
These new genotypes are characterized as 4 + 4 reassortants, with B3.13 retaining certain genetic segments from the Eurasian lineage A1, and D1.1 retaining segments from the Eurasian lineage A3. Despite its late emergence, D1.1 quickly became the prevalent genotype among migratory wild birds in the Americas.
Late 2024 saw alarming reports linking the D1.1 genotype to severe illnesses in two cases, one in British Columbia, Canada, and the other in Louisiana, US, with the Louisiana case resulting in fatality. Adding to public health concerns, D1.1 was introduced into dairy cattle in January 2025, raising alarms over potential spillover into humans and other mammals.
Reports from the United States highlight the extensive distribution and transmissibility of the newly identified HPAI H5N1 genotypes, B3.13 and D1.1, in dairy cattle. This broadened host range signifies a critical threat, particularly as both genotypes display an ability to infect the respiratory tract of calves and the mammary glands of dairy cows, leading to mastitis and considerable declines in milk production.
The ongoing outbreaks raise food safety concerns and pose risks of adaptation and transmission to humans and non-human mammals, including domestic cats, alpacas, goats, and rodents.
Since the initial outbreak of HPAI H5N1 in March 2024 until June 2025, approximately 13,225 wild birds, 175 million poultry, and 1,075 dairy herds across 17 states in the US have reported infections. The B3.13 genotype’s transmission to cattle was linked with multiple virulence-determinant mutations in various viral proteins, which may increase virulence in mammals, thus compounding the potential public health impact.
These genetic changes at the mammalian-bovine interface, coupled with the segmented nature of avian influenza viruses, raise concerns about reassortment with other viruses. Such changes could facilitate adaptations that enhance the virus’s fitness, pathogenicity, and transmissibility among mammals, including potential zoonotic risks.
To tackle these concerns, the US employs specific regulatory protocols for managing HPAI H5N1 transmission across state lines, especially regarding dairy cattle. Testing is mandatory at accredited laboratories for all cattle intended for interstate movement, with only animals testing negative permitted for transport.
In the unfortunate event of a positive test, herd owners must provide detailed epidemiological data, including movement histories, to aid disease tracking and containment efforts. Enhanced biosecurity measures have shown a significant reduction in interstate and outbreak reports tied to HPAI H5N1 since the imposition of these measures in dairy cattle.
Unlike poultry farms where birds are typically confined, dairy cattle often graze or are housed outdoors, increasing contact with migratory birds. Although thus far, the genotypes remain confined to North America, their potential spread to other regions, particularly Latin America, calls for heightened vigilance and improved serological and etiological surveillance.
The complex epidemiological conditions leading to new transmission events in the US suggest possible deficiencies in biosecurity and surveillance on dairy farms. Furthermore, concerns linger that robust surveillance might hinder dairy business operations, potentially limiting collaboration and data collection vital for controlling subsequent outbreaks.
Currently, interventions for managing HPAI H5N1 human infections in the US include the use of antiviral treatments, continuous surveillance for high-risk populations, and enhanced biosecurity measures to limit transmission. In dairy cattle, efforts focus on biosecurity improvements, strict animal movement restrictions, and testing requirements prior to transport.
Conversely, poultry farms mainly resort to culling infected flocks while maintaining strict biosecurity protocols. To date, no vaccination programs have been approved within the US for dairy cattle or high-risk dairy farm workers despite the widespread presence of the B3.13 and D1.1 genotypes.
However, a conditional license for an inactivated H5N2 vaccine for use in chickens has been granted, showcasing some vaccination efforts. The integration of this vaccine is crucial due to its role in providing specific antibody protection and differentiating vaccinated poultry from naturally infected counterparts.
Immunizations in poultry have proven effective in lessening virus transmission risks to mammals, yet dairy herds continue to suffer significant losses due to asymptomatic infections and a lack of focused vaccination strategies.
The USDA and the CDC are working towards vaccine development for both cattle and humans, advocating for novel vaccine candidates to mitigate zoonotic risks associated with HPAI H5N1 infections. Current World Health Organization (WHO) recommendations suggest specific candidate viral strains against the circulating HPAI H5N1 strains.
Globally, the uptake of vaccination against HPAI H5N1 is present but limited, with Finland as one of the few countries actively implementing targeted vaccination campaigns for high-risk groups.
Multiple inactivated H5 vaccines have received licenses worldwide, and various innovative vaccination approaches, including live-attenuated and mRNA-based solutions, are progressing through research and clinical trials.
Four FDA-approved antiviral medications currently exist, effectively targeting influenza activity on multiple fronts. While vigilance continues, one isolate has shown reduced susceptibility, underscoring the need for continual monitoring of both medications and emerging strains.
The present resurgence of the B3.13 and D1.1 genotypes of the 2.3.4.4b HPAI H5N1 virus presents a complex public health challenge requiring a cohesive response.
Shifting focus to the One Health approach, a collaboration among various sectors is vital to unearth systemic surveillance, deploy credible epidemiological reporting, and implement preventive measures, including vaccination.
The dual challenges of the wild bird-to-poultry transmission and recent spillovers into cattle highlight the necessity for tailored strategies addressing HPAI H5N1 outbreaks. Continuous support for research and collaboration with international organizations must be reinforced to mitigate the threat of future pandemic crises.
Going forward, the vigilance against zoonotic transmission of these avian influenza viruses to humans remains critical, advocating for robust measures to safeguard both public and animal health.
image source from：nature
