Write a PREreview

Influenza A viruses in swine have considerable genetic diversity and continue to pose a pandemic threat to humans. They were the source of the most recent influenza pandemic, and since 2010, novel swine viruses have spilled over into humans more than 400 times in the United States. Although these zoonotic infections generally result in mild illness with limited onward human transmission, the potential for sustained transmission of an emerging influenza virus between individuals due to lack of population level immunity is of great concern. Compiling the literature on pandemic threat assessment, we established a pipeline to characterize and triage influenza viruses for their pandemic risk and examined the pandemic potential of two widespread swine origin viruses. Our analysis revealed that a panel of human sera collected from healthy adults in 2020 has no cross-reactive neutralizing antibodies against an α-H1 clade strain but do against a γ-H1 clade strain. Swine H1N2 virus from the α-H1 clade (α-swH1N2) replicated efficiently in human airway cultures and exhibited phenotypic signatures similar to the human H1N1 pandemic strain from 2009 (H1N1pdm09). Furthermore, α-swH1N2 was capable of efficient airborne transmission to both naïve ferrets and ferrets with prior seasonal influenza immunity. Ferrets with H1N1pdm09 pre-existing immunity had reduced α-swH1N2 viral shedding from the upper respiratory tract and cleared the infection faster. Despite this, H1N1pdm09-immune ferrets that became infected via the air could still onward transmit α-swH1N2 with an efficiency of 50%. Taken together, these results indicate that this α-swH1N2 strain has a higher pandemic potential, but a moderate level of impact since there is reduced replication fitness in animals with prior immunity.