Mammalian Pathogenesis and Transmission of H7N9 Influenza Viruses from Three Waves, 2013-2015

Three waves of human infection with H7N9 influenza viruses have concluded to date, but only viruses within the first wave (isolated between March and September 2013) have been extensively studied in mammalian models. While second-and third-wave viruses remain closely linked phylogenetically and antigenically, even subtle molecular changes can impart critical shifts in mammalian virulence. To determine if H7N9 viruses isolated from humans during 2013 to 2015 have maintained the phenotype first identified among 2013 isolates, we assessed the ability of first-, second-, and third-wave H7N9 viruses isolated from humans to cause disease in mice and ferrets and to transmit among ferrets. Similar to first-wave viruses, H7N9 viruses from 2013 to 2015 were highly infectious in mice, with lethality comparable to that of the well-studied A/Anhui/1/2013 virus. Second-and third-wave viruses caused moderate disease in ferrets, transmitted efficiently to cohoused, naive contact animals, and demonstrated limited transmissibility by respiratory droplets. All H7N9 viruses replicated efficiently in human bronchial epithelial cells, with subtle changes in pH fusion threshold identified between H7N9 viruses examined. Our results indicate that despite increased genetic diversity and geographical distribution since their initial detection in 2013, H7N9 viruses have maintained a pathogenic phenotype in mammals and continue to represent an immediate threat to public health.