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Human-to-swine transmission of influenza A (H3N2) virus occurs repeatedly and plays a critical role in swine influenza A virus (IAV) evolution and diversity. Human seasonal H3 IAVs were introduced from human-to-swine in the 1990s in the United States and classified as 1990.1 and 1990.4 lineages; the 1990.4 lineage diversified into 1990.4.A–F clades. Additional introductions occurred in the 2010s, establishing the 2010.1 and 2010.2 lineages. Human zoonotic cases with swine IAV, known as variant viruses, have occurred from the 1990.4 and 2010.1 lineages, highlighting a public health concern. If a variant virus is antigenically drifted from current human seasonal vaccine (HuVac) strains, it may be chosen as a candidate virus vaccine (CVV) for pandemic preparedness purposes. We assessed the zoonotic risk of US swine H3N2 strains by performing phylogenetic analyses of recent swine H3 strains to identify the major contemporary circulating genetic clades. Representatives were tested in hemagglutination inhibition assays with ferret post-infection antisera raised against existing CVVs or HuVac viruses. The 1990.1, 1990.4.A, and 1990.4.B.2 clade viruses displayed significant loss in cross-reactivity to CVV and HuVac antisera, and interspecies transmission potential was subsequently investigated in a pig-to-ferret transmission study. Strains from the three lineages were transmitted from pigs to ferrets via respiratory droplets, but there were differential shedding profiles. These data suggest that existing CVVs may offer limited protection against swine H3N2 infection, and that contemporary 1990.4.A viruses represent a specific concern given their widespread circulation among swine in the United States and association with multiple zoonotic cases. [ABSTRACT FROM AUTHOR]

During the last decade, endemic swine H1 influenza A viruses (IAV) from six different genetic clades of the hemagglutinin gene caused zoonotic infections in humans. The majority of zoonotic events with swine IAV were restricted to a single case with no subsequent transmission. However, repeated introduction of human-seasonal H1N1, continual reassortment between endemic swine IAV, and subsequent drift in the swine host resulted in highly diverse swine IAV with human-origin genes that may become a risk to the human population. To prepare for the potential of a future swine-origin IAV pandemic in humans, public health laboratories selected candidate vaccine viruses (CVV) for use as vaccine seed strains. To assess the pandemic risk of contemporary US swine H1N1 or H1N2 strains, we quantified the genetic diversity of swine H1 HA genes, and identified representative strains from each circulating clade. We then characterized the representative swine IAV against human seasonal vaccine and CVV strains using ferret antisera in hemagglutination inhibition assays (HI). HI assays revealed that 1A.3.3.2 (pdm09) and 1B.2.1 (delta-2) demonstrated strong cross reactivity to human seasonal vaccines or CVVs. However, swine IAV from three clades that represent more than 50% of the detected swine IAVs in the USA showed significant reduction in cross-reactivity compared to the closest CVV virus: 1A.1.1.3 (alpha-deletion), 1A.3.3.3-clade 3 (gamma), and 1B.2.2.1 (delta-1a). Representative viruses from these three clades were further characterized in a pig-to-ferret transmission model and shown to exhibit variable transmission efficiency. Our data prioritize specific genotypes of swine H1N1 and H1N2 to further investigate in the risk they pose to the human population. [ABSTRACT FROM AUTHOR]