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Abstract
Swine influenza A viruses (swIAVs) pose a large economic burden on commercial swine production as well as a public health risk to human populations. Variant swIAVs annually infect humans in limited spillover events that indicate the potential for a future pandemic. Crucial to preempting these events is the establishment of a rigorous threat assessment framework for human populations. Utilizing animal models as well as primary cell culture systems our lab completed an assessment of a recent swIAV isolate, A/swine/GA/A27480/19. Our studies provided evidence that this virus may pose a risk to humans by demonstrating an ability to infect the human-derived Calu-3 cell line as well as naïve ferrets, which are widely used as a surrogate model for human infection and transmission. Critically, without adaptation to the ferret host the swine isolate was able to transmit to cohoused contact animals. Having established a health risk from the isolate we further investigated vaccine strategies within the weanling pig model. Vaccination with inactivated viruses related to the A/swine/GA/A27480/19 isolate has previously been found to result in vaccine-associated enhanced respiratory disease (VAERD) upon challenge with a heterologous virus. We developed a model of VAERD using the A/swine/GA/A27480/19 virus and A/California/04/2009 mismatch, further demonstrating a means of reducing pathology by mucosal priming with the virus. An intranasal route of inoculation was found to increase the number of tissue-resident T cells within the respiratory tract of animals compared to intramuscular vaccination. Characterization of the serological antibody responses after intramuscular or intranasal priming showed a non-neutralizing antibody response that may enhance viral replication within the host, however those animals that were able to also mount a tissue-resident cell-mediated response at the mucosal interface were protected from VAERD. Together our studies provide evidence for a health risk posed to both humans and swine by an emerging lineage of swIAVs, and demonstrate the importance of mucosal immune responses in effective protection of weanling pigs from future influenza challenges.