Editorial: Characteristics and Prevention of the Emerging Avian Influenza A Viruses in Birds and Mammals

Jinyu Sui Kaicheng Wang ^*

• China Animal Health and Epidemiology Center, Qingdao, China

Avian influenza A virus(AIV) has circulated widely in domestic poultry and wild birds. Especially since 2021, the highly pathogenic avian influenza (HPAI) H5 virus has led to mass deaths and slaughter of poultry, peaking at 146 million in 2022 (WOAH, 2024), and the wild bird HPAI cases has had the widest geographical spread in 76 countries and territories around the world, with 101,817 wild bird cases, a historically unprecedented occurrence (WOAH,2024). Additionally, HPAI H5 virus has increasingly crossed species barrier, and more than 70 mammalian species infected with H5 virus have been reported to the World Organisation for Animal Health(WOAH) with over 1100 cumulative outbreak records since 2021, including marine mammals, terrestrial carnivorous and scavenging mammals, livestocks as well as domestic cats and dogs (WOAH, 2025). In 2024, an unprecedented outbreak of HPAI H5N1 in dairy herds occurred in the USA, as of November 2025, 928 infected dairy herds had confirmed in 16 states, with virus spread within and between herds, infections in poultry and cats, and spillover into humans(Figure 1)(US CDC, 2025).Meanwhile, with the increasing number of infected mammalian species, mammal-to-mammal transmission may have occurred during outbreaks of H5N1 viruses in minks, sea lions and cows (Eisfeld et al., 2024).This trend is particularly concerning as it indicates that the viruses may be evolving to adapt more effectively to mammalian hosts. (Table 1) (WOAH, 2024).In 2024, an unprecedented outbreak of HPAI H5N1 in dairy herds occurred in the USA, with virus spread within and between herds, infections in poultry and cats, and spillover into humans 40 human cases associated with exposure to sick dairy cows had been reported to be infected with HPAI H5 avian influenza viruses(US CDC, 2025). The primary risk factor for human infection is exposure to infected live or dead birds or contaminated environments. In contrast, the CFR was much higher in those with a history of exposure to sick and dead birds compared to the other exposure groups, which may be related to the higher viral loads carried by the sick and dead birds (Li et al., 2024a).The HAs of AIV strains show a preference for α2,3-linked sialic acids (SA-α2,3-Gal), whereas the HAs of human influenza virus strains bind preferentially to α2,6-linked sialic acids(SA-α2,6-Gal). Human tracheal epithelium expresses mainly SA-α2,6-Gal, and alveoli and bronchioles expresses mainly SA-α2,3-Gal.Consequently, severe pneumonia is the common lesion in the human cases with confirmed H5N1 virus infection. (Van Riel, 2007；Jassem, 2024). Notably, the bovine H5N1 virus was found to bind to SA-α2,6-Gal in human upper airways while still exhibiting a strong preference for avian-like SA-α2,3-Gal. In addition, bovine H5 strongly binds both bovine and human tissues such as conjunctival, bronchioles, lung, and mammary gland, is consistent with the reported clinical symptoms in cattle, which include respiratory distress and mammary gland inflammation. (Garg, 2024;Song, 2025). PB2 protein can enhance replication efficiency and adaptability to mammalian hosts.The sequences of AIVs from the human and mammalian cases had key molecular markers associated with mammalian adaptation and pathogenicity, particularly in the HA and PB2 gene segments. For example, HA T192I, PB2 Q591K, D701N and E627K in the H5N1 viruses.(FAO/WHO/WOAH, 2024); HA G186V and Q226L/I, PB2 E627K, D701N and K702R in the H7N9 viruses(WHO, 2018); HA Q226L, PB2 E627K, D701N in the H9N2 viruses (Tan et al., 2023). The PB2 E627K and HA E186D and Q222H mutations that potentially associated with enhanced virulence and human adaptation, were identified in the genome of a Canadian case who presented with conjunctivitis and fever and progressed to respiratory failure (Jassem, 2024). The PB2 E627K mutation was also identified in the genome of the human case with exposure to infected dairy cows.(FAO/WHO/WOAH, 2024). Although the species barrier largely restricts the cross-species transmission of AIVs, these mutations increase the binding ability with SA-α2,6-Gal and facilitate mammalian adaptation.To date, AIV strains detected in humans and mammals have not established adaptations to mammalian hosts or acquired the capacity for sustained human-to-human transmission. All reported human cases have occurred after exposure to infected animals or contaminated environment. Based on the information reported, the joint assessment by the Food and Agriculture Organization of the United Nations(FAO)-WHO-WOAH concludes that the global public health risk of HPAI H5/H7 viruses remains low(WHO, 2018; FAO/WHO/WOAH, 2024).However, HPAIV remains a significant global challenge due to its widespread circulation and the dramatic increase of spillovers between wild birds and mammals.Several preventive measures against the AIVs are required for averting potential he PB2 E627K mutation was also identified in the genome of the human isolate associated with exposure to infected dairy cowsIf such adaptive mutations are maintained in mammals, it may increase the possibility of novel strains emerging that are not only highly transmissible but also pose a significant pathogenic threat to both humans and mammals.In the cases identified to date, A(H5N1) viruses generally caused mild illness, mostly conjunctivitis, of short duration, but 删除[user]: future influenza pandemics, including:1.Stronger global surveillance among wild birds, poultry, mammals and humans is central to informing the threat of HPAIVs.Fair et al. present a series of recommendations to strengthen wild bird surveillance through a more connected network, 2.Vaccination is an important strategy for the control of HPAIVs, and it is essential to continue evaluating candidate vaccine viruses in order to prepare for pandemics. A study proposes a novel computational method for predicting antigenic distances, which exhibits low error in viruses antigenicity prediction and achieves superior accuracy in discerning antigenic drift (Li et al., 2024b), 3.The constantly evolving genome of AIV poses a challenge for effective antiviral therapeutics due to mutations in the viruses, particularly those on the surface protein such as HA and neuraminidase (NA). Previous studies revealed that the double or triple combinations of antiviral drugs or antibodies contribute to synergistic antiviral activity against a panel of AIVs (Hoang et al., 2024).The contributions in this Research Topic underscore the characteristics and prevention of HPAIV in birds and mammals. It is recommended that future research focus on additional studies or surveillance to contain the elevated public health risk posed by the widespread distribution and ongoing evolution of AIVs.