Transmission of a human isolate of clade 2.3.4.4b A(H5N1) virus in ferrets.

Since 2020, there has been unprecedented global spread of highly pathogenic avian influenza A(H5N1) in wild bird populations with spillover into a variety of mammalian species and sporadically humans. In March 2024, clade 2.3.4.4b A(H5N1) virus was first detected in dairy cattle in the USA, with subsequent detection in numerous states, leading to more than a dozen confirmed human cases. In this study, we used the ferret, a well-characterized animal model that permits concurrent investigation of viral pathogenicity and transmissibility, in the evaluation of A/Texas/37/2024 (TX/37) A(H5N1) virus isolated from a dairy farm worker in Texas. Here we show that the virus has a remarkable ability for robust systemic infection in ferrets, leading to high levels of virus shedding and spread to naive contacts. Ferrets inoculated with TX/37 rapidly exhibited a severe and fatal infection, characterized by viraemia and extrapulmonary spread. The virus efficiently transmitted in a direct contact setting and was capable of indirect transmission through fomites. Airborne transmission was corroborated by the detection of infectious virus shed into the air by infected animals, albeit at lower levels compared to those of the highly transmissible human seasonal and swine-origin H1 subtype strains. Our results show that despite maintaining an avian-like receptor-binding specificity, TX/37 exhibits heightened virulence, transmissibility and airborne shedding relative to other clade 2.3.4.4b virus isolated before the 2024 cattle outbreaks, underscoring the need for continued public health vigilance.