Pigs are highly susceptible to but do not transmit mink-derived highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b

Rapid evolution of highly pathogenic avian influenza viruses (HPAIVs) is driven by antigenic drift but also by reassortment, which might result in robust replication in and transmission to mammals. Recently, spillover of clade 2.3.4.4b HPAIV to mammals including humans, and their transmission between mammal species has been reported. This study aimed to evaluate the pathogenicity and transmissibility of a mink-derived clade 2.3.4.4b H5N1 HPAIV isolate from Spain in pigs. Experimental infection caused moderate to severe interstitial pneumonia with necrotizing bronchiolitis with high titers of virus present in the lower respiratory tract of principal-infected pigs and 100% seroconversion. Principal-infected pigs shed limited amount of virus through the nasal and oral cavities, and importantly, there was no transmission to contact sentinel pigs. Notably, critical mammalian-like mutations such as PB2-E627K and HA-Q222L emerged at low frequencies in clinical samples and tissues derived from principal-infected pigs. It is concluded that pigs are highly susceptible to infection with the mink-derived clade 2.3.4.4b H5N1 HPAIV and provide a favorable environment for HPAI viruses to acquire mammalian-like adaptations. This work is critical for further risk assessment on the ability of the newly emerging H5N1 clade 2.3.4.4b HPAIVs to cross the species barriers into mammals. ### Competing Interest Statement The J.A.R. laboratory received support from Tonix Pharmaceuticals, Genus plc, Xing Technologies, and Zoetis, outside of the reported work. J.A.R. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections, owned by Kansas State University. The other authors declare no competing interests.