Highly Pathogenic Avian Influenza (HPAI) H5 Clade 2.3.4.4b Virus Infection in Birds and Mammals

Simple Summary Avian influenza viruses are highly contagious respiratory viruses that severely impact bird populations, causing significant morbidity, mortality, and economic losses in the poultry industry worldwide. Particularly concerning are the Asian-origin H5 subtype highly pathogenic avian influenza viruses of clade 2.3.4.4b, which emerged in 2013 and have since spread across Asia, Europe, Africa, and America, leading to outbreaks in various poultry and animal species. The unique epidemiological and pathobiological characteristics specific to clade 2.3.4.4b viruses are discussed, emphasizing their distinct nature compared to other clades. Wild waterfowl, acting as reservoirs, frequently carry these viruses, posing threats not only to their populations but also to other wild bird species, including endangered ones. Furthermore, an increasing number of clade 2.3.4.4b virus infections in wild or domestic mammalian species raises significant concerns about potential spillover events to humans. This review highlights the diverse outcomes of HPAI infections in different hosts, ranging from asymptomatic cases to fatal infection, influenced by host and virus-related factors. Understanding these complexities is vital for developing effective strategies to mitigate the impact of AIVs, safeguard poultry production, protect wildlife, and prevent potential public health crises.Abstract Avian influenza viruses (AIVs) are highly contagious respiratory viruses of birds, leading to significant morbidity and mortality globally and causing substantial economic losses to the poultry industry and agriculture. Since their first isolation in 2013-2014, the Asian-origin H5 highly pathogenic avian influenza viruses (HPAI) of clade 2.3.4.4b have undergone unprecedented evolution and reassortment of internal gene segments. In just a few years, it supplanted other AIV clades, and now it is widespread in the wild migratory waterfowl, spreading to Asia, Europe, Africa, and the Americas. Wild waterfowl, the natural reservoir of LPAIVs and generally more resistant to the disease, also manifested high morbidity and mortality with HPAIV clade 2.3.4.4b. This clade also caused overt clinical signs and mass mortality in a variety of avian and mammalian species never reported before, such as raptors, seabirds, sealions, foxes, and others. Most notably, the recent outbreaks in dairy cattle were associated with the emergence of a few critical mutations related to mammalian adaptation, raising concerns about the possibility of jumping species and acquisition of sustained human-to-human transmission. The main clinical signs and anatomopathological findings associated with clade 2.3.4.4b virus infection in birds and non-human mammals are hereby summarized.