Leveraging the Ferret Model for understanding H5N1 2.3.4.4b virus pathogenesis in preimmune populations and mammary glands

Highly Pathogenic Avian Influenza (HPAI) virus subtype H5N1 is a significant health threat to humans, livestock, and wild animals worldwide. H5N1 clade 2.3.4.4b has recently caused a significant outbreak in US Dairy Cattle with spillover events in humans; however, we currently have little understanding of the potential of H5N1 2.3.4.4b to infect Canadians as well as Canadian cattle. Due to pre-existing immunity in humans from seasonal H1N1 or H3N2 infections or influenza vaccination, the true risk of cattle-origin H5N1 is unknown and it is possible that people may be protected from disease depending on their previous infections. Additionally, the dynamics of H5N1 infection, transmission, and immunity in the Dairy Cattle mammary gland is not known. Importantly, there are no H5N1 vaccines in use for cows or people. Studying infection and vaccination in H5N1 infected dairy cattle in high containment labs is dangerous and almost impossible due to the large space needed and the difficulty finding cattle for experiments. Ferrets are a potential solution to this problem since they are the gold standard model for studying influenza. Our team of researchers has the expertise in influenza virus pathogenesis, mammary gland immunology, and bovine infection to address the unknowns. Using ferrets, we will determine if previous infection or vaccination can protect against severe disease from Dairy Cattle H5N1. In our second investigation we will use the ferret lactating influenza model and infect the lactating mammary glands with H5N1. By studying the virus that is shed in milk, the cells that are infected, and the associated immune responses we hope to identify when infection is most contagious and ways we can stop the virus transmission chain. Taken together, this work will bring valuable insight on mechanisms of Dairy Cattle H5N1 infection, highlight potential therapeutic interventions, and provide a tool to evaluate vaccines and antivirals as these become available.