Avian influenza A viruses rarely infect humans; however, when human infection and subsequent human-to-human transmission occurs, worldwide outbreaks (pandemics) can result. The recent sporadic infections of humans in China with a previously unrecognized avian influenza A virus of the H7N9 subtype (A(H7N9)) have caused concern owing to the appreciable case fatality rate associated with these infections (more than 25%), potential instances of human-to-human transmission1, and the lack of pre-existing immunity among humans to viruses of this subtype. Here we characterize two early human A(H7N9) isolates, A/Anhui/1/2013 (H7N9) and A/Shanghai/1/2013 (H7N9); hereafter referred to as Anhui/1 and Shanghai/1, respectively. In mice, Anhui/1 and Shanghai/1 were more pathogenic than a control avian H7N9 virus (A/duck/Gunma/466/2011 (H7N9); Dk/GM466) and a representative pandemic 2009 H1N1 virus (A/California/4/2009 (H1N1pdm09); CA04). Anhui/1, Shanghai/1 and Dk/GM466 replicated well in the nasal turbinates of ferrets. In nonhuman primates, Anhui/1 and Dk/GM466 replicated efficiently in the upper and lower respiratory tracts, whereas the replicative ability of conventional human influenza viruses is typically restricted to the upper respiratory tract of infected primates. By contrast, Anhui/1 did not replicate well in miniature pigs after intranasal inoculation. Critically, Anhui/1 transmitted through respiratory droplets in one of three pairs of ferrets. Glycan arrays showed that Anhui/1, Shanghai/1 and A/Hangzhou/1/2013 (H7N9) (a third human A(H7N9) virus tested in this assay) bind to human virus-type receptors, a property that may be critical for virus transmissibility in ferrets. Anhui/1 was found to be less sensitive in mice to neuraminidase inhibitors than a pandemic H1N1 2009 virus, although both viruses were equally susceptible to an experimental antiviral polymerase inhibitor. The robust replicative ability in mice, ferrets and nonhuman primates and the limited transmissibility in ferrets of Anhui/1 suggest that A(H7N9) viruses have pandemic potential.
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We thank Y. Shu for A/Anhui/1/2013 (H7N9) and A/Shanghai/1/2013 (H7N9) viruses. We thank the IMSUT serum bank for providing human sera. We thank R. Webster for providing monoclonal antibody to A/seal/Massachusetts/1/80 (H7N7). Polyclonal anti-influenza virus H7 HA, A/Netherlands/219/2003 (H7N7) (anti-serum, goat) NR-9226, was obtained through the National Institutes of Health (NIH) Biodefense and Emerging Infections Research Resources Repository, National Institute of Allergy and Infectious Diseases (NIAID), NIH. We thank S. Watson for editing the manuscript, T. Suzuki, K. Takahashi, S. Fujisaki and H. Xu for discussions, and Y. Sato, H. Sugawara, A. Sato, M. Ejima and T. Miura for technical assistance. We thank Toyama Chemical Co. for providing favipiravir, Daiichi Sankyo Co. for providing laninamivir, F. Hoffmann-La Roche for providing oseltamivir carboxylate, GlaxoSmithKline for providing zanamivir and Shionogi & Co. for providing peramivir. This work was supported by the Japan Initiative for Global Research Network on Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by grants-in-aid from the Ministry of Health, Labour and Welfare, Japan; by ERATO (Japan Science and Technology Agency); by NIAID Public Health Service research grants AI099274 and AI058113 to J.C.P., and by an NIAID-funded Center for Research on Influenza Pathogenesis (CRIP, HHSN266200700010C) to Y.K.
This file contains Supplementary Results, Supplementary Figures S1-S11, Supplementary Tables S1-S18 and a Supplementary Reference.
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Stem Cell Reports (2019)