Dynamics of a Panzootic: Genomic Insights, Host Range, and Epidemiology of the Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b in the United States

In late 2021, Eurasian-lineage highly pathogenic avian influenza (HPAI) A(H5N1) viruses from HA clade 2.3.4.4b were first detected in the United States. These viruses have caused severe morbidity and mortality in poultry and have been detected in numerous wild and domestic animals, including cows and humans. Notably, infected cows transmitted the virus to cats, causing extreme pathogenicity and death. While human-to-human spread of the virus has not been recorded, efficient transmission of the bovine-origin virus has also led to extreme pathogenicity and death in ferret models. Recently, markers in PB2 (E627K) and HA (E186D, Q222H), indicating mammalian adaptation mutations, were detected in an H5N1-infected patient manifesting critical illness in Canada. These, combined with instances of interspecies spread of the virus, have raised global public health concerns. This could highlight the potential for the virus to successfully adapt to mammals, posing a serious risk of a global outbreak. A One Health approach is, thereby, necessary to monitor and control the outbreak. This review aims to analyze the epidemiology, transmission, and ecological impacts of HPAI A(H5N1) clade 2.3.4.4b in the U.S., identify knowledge gaps, and inform strategies for effective outbreak management and mitigation.