H5N1 bird flu is mutating fast and jumping to mammals - could the next pandemic be here?

By Dr. Sanchari Sinha Dutta, Ph.D.Sep 25 2024

Scientists have uncovered alarming evidence of H5N1’s rapid adaptation to mammals fueled by genetic mutations. With mammal-to-mammal transmission now confirmed, could this be the precursor to the next global pandemic?

Review: The global H5N1 influenza panzootic in mammals. Image Credit: Rui Duarte / Shutterstock

In a review article published in the journal Nature, the authors describe molecular and ecological factors associated with the sudden expansion of H5N1 high-pathogenicity avian influenza (HPAI) viruses in mammals.

Background

Influenza A viruses are associated with most of the documented global pandemics in human history. High pathogenicity avian influenza (HPAI) viruses belonging to the H5N1 subtype are a leading risk factor for future pandemics. The evolutionary barriers to mammalian adaptation of these viruses are lower than previously thought, as shown by rapid mutation accumulation in key viral proteins.

H5N1 viruses were initially detected only in Asian poultries during the past two decades. However, in recent years, a rapid transmission of these viruses into new mammal species has been observed worldwide, endangering wildlife, agricultural production, and human health.

Such rapid viral transmission started after the emergence of a new genotype of H5N1 viruses belonging to clade 2.3.4.4b, which infected wild birds from Europe to Africa, North America, South America, and the Antarctic. These viruses arose from genomic reassortment between the H5N8 and low-pathogenicity avian influenza (LPAI) viruses, generating new hybrid strains.

The genomic reassortment event between 2.3.4.4b H5N8 and low pathogenicity avian influenza (LPAI) viruses gave rise to the panzootic 2.3.4.4b H5N1 viruses, which are genetically different from prior strains. This reassortment involved the polymerase gene and surface proteins, facilitating rapid adaptation to new environments.

The panzootic 2.3.4.4b H5N1 viruses can silently transmit to new countries or continents through migrating aquatic wild birds. This may result in mass die-offs among social sea birds congregating in large, dense colonies. Birds of prey or animals that eat dead H5N1-infected birds can also die due to neurological disorders. Viral spillover to mammals has been linked to several adaptive mutations that enhance viral replication in mammalian hosts, specifically within the polymerase (PB2) and hemagglutinin (HA) genes.

In this review article, the authors discuss influenza A virus spillover and H5N1 pandemic potential by analyzing three H5N1 case studies demonstrating mammal-to-mammal transmission.

The article provides information on the acquisition of key adaptive mutations that enabled 2.3.4.4b H5N1 viruses to sustain mammal-to-mammal transmission. The authors have collected this information from three real-world settings: the 2022-2023 H5N1 outbreaks on European fur farms, the 2023 South American marine mammal-adapted virus, and the 2024 US dairy cattle outbreak.

H5N1 outbreaks on European fur farms

The evidence collected from H5N1-infected European farmed animals (American mink, arctic foxes, and raccoon dogs) revealed the presence of known mammalian-adaptive mutations in the PB2 gene, particularly the PB2 E627K mutation, which enhances viral replication in mammals.

Mammal-to-mammal transmission was suspected based on the close genetic relatedness of the viruses found on different farms. Experimental studies confirmed the effective transmission of the viruses between ferrets in direct contact. This genetic proximity is consistent with sustained transmission driven by adaptive changes in the polymerase complex.

Farm-to-farm transmission most probably occurred due to the movement of contaminated equipment, clothing, or infected carcasses fed to other mink. The new reassortant H5N1 genotype, “BB,” which emerged in 2022, represents a hybrid virus combining genome segments from prior H5N1 and LPAI gull-adapted viruses. This genotype caused mass die-offs in black-headed gulls throughout Europe.

Genetic sequencing revealed that the H5N1 viruses belong to a new reassortant H5N1 genotype, “BB,” that emerged in 2022 and caused mass die-offs in black-headed gulls throughout Europe.

An H5N1 outbreak also occurred in Poland in mid-2023, killing more than 30 domestic cats. Raw pet foods sourced from mink farms were assumed to be a potential source of the virus. Sequencing of cat-derived H5N1 viruses revealed identical mammalian adaptations absent in avian viruses circulating in Europe at the time.  The cat-derived H5N1 viruses shared identical mammalian-adaptive mutations in PB2 (E627K, D701N), highlighting the virus’s ability to adapt across different mammalian hosts.

H5N1 outbreaks in South American marine mammals

A new reassortant H5N1 genotype B3.2 arrived from North America to South America in late 2022, causing mass die-offs in coastal birds and marine mammals.

Genetic sequencing of H5N1 viruses from South American marine mammals identified the same known mammalian adaptations (PB2 D701N and Q591K) and other distinctive mutations absent in birds, supporting mammal-to-mammal transmission.

The B3.2 viruses in the marine mammal clade were also identified in South American sea lions, common dolphins, Chilean dolphins, porpoises, sea otters, fur seals, elephant seals, and one human. These mutations allowed the virus to exploit mammalian cellular machinery, facilitating sustained transmission in a mammalian host.

The hospitalized man resided near a beach with H5N1-infected animals, and the virus derived from the infected man also contained the same two mammalian adaptations found in pinnipeds, indicating the environmental mode of transmission of the virus.

A spillback of mammalian-adapted B3.2 viruses from marine mammals to wild birds was also observed in South America. However, no reversions were observed in the mammalian-adapted PB2 mutations, demonstrating the virus’s strong adaptation to mammalian hosts.

H5N1 outbreaks in US dairy cattle

The H5N1 viruses belonging to the B3.13 genotype were identified as causative pathogens associated with Texas dairy cattle outbreaks in 2024. Phylogenetic analysis showed a single viral introduction from wild birds into cattle. Mammalian-adaptive mutations PB2 M631L and PA K497R were detected in the cattle clade, facilitating increased replication in mammalian cells.

Only four B3.13 genotype viruses were identified in US wildlife apart from the cattle clade, suggesting that this genotype is rare in wild birds. The viruses' high genetic diversity points to rapid local evolution in dairy cattle, providing further evidence of sustained mammalian transmission.

The high genetic diversity of the H5N1 virus in Texas cattle suggests that the bovine B3.13 outbreak originated in Texas and rapidly spread to additional states. Transport of infected cattle or equipment was considered the most likely cause of viral transmission.

Cattle-origin H5N1 viruses were also identified in other species, including domestic cats, alpacas, wild birds, terrestrial mammals, and poultry. Transmission routes likely include milk contamination due to the virus’s mammary tissue tropism, leading to widespread infection through contaminated milk. Thirteen human cases, including four dairy farm workers, were also identified in the US.

Less than 20 human cases of 2.3.4.4b H5N1 viruses have been documented in Europe and the US since 2020, a low number compared to the H5N1 human cases recorded in Asia and Egypt in 2015.

Significance

The potency of H5N1 viruses in creating future pandemics remains unknown. Recent human cases with H5N1 2.3.4.4b viruses have significantly lower fatality rates than prior H5N1 outbreaks in Asia.

If H5N1 continues spreading in humans, an existing H5 vaccine that is antigenically related to circulating 2.3.4.4b viruses can be scaled up using mRNA platforms.  However, the virus’s ability to reassort with other influenza viruses, particularly in high-risk settings such as farms, raises concerns about the potential for more transmissible variants.