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.

Author information

Author notes

    • Tokiko Watanabe
    • , Maki Kiso
    • , Satoshi Fukuyama
    • , Noriko Nakajima
    •  & Masaki Imai

    These authors contributed equally to this work.


  1. ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan

    • Tokiko Watanabe
    • , Satoshi Fukuyama
    • , Dongming Zhao
    • , Yuriko Tomita
    • , Naomi Fujimoto
    • , Kazue Goto
    • , Eiryo Kawakami
    • , Izumi Ishikawa
    • , Shinji Watanabe
    •  & Yoshihiro Kawaoka
  2. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

    • Maki Kiso
    • , Shinya Yamada
    • , Seiya Yamayoshi
    • , Kiyoko Iwatsuki-Horimoto
    • , Takeshi Noda
    • , Hiroaki Katsura
    • , Mutsumi Ito
    • , Yuko Sakai-Tagawa
    • , Yukihiko Sugita
    • , Ryuta Uraki
    • , Reina Yamaji
    •  & Yoshihiro Kawaoka
  3. Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo 162-8640, Japan

    • Noriko Nakajima
    •  & Hideki Hasegawa
  4. Influenza Virus Research Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo 208-0011, Japan

    • Masaki Imai
    • , Emi Takashita
    • , Noriko Kishida
    • , Masayuki Shirakura
    • , Takato Odagiri
    •  & Masato Tashiro
  5. Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

    • Shin Murakami
    •  & Yoshihiro Kawaoka
  6. Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan

    • Yoshihiro Sakoda
    • , Shintaro Shichinohe
    • , Masatoshi Okamatsu
    • , Tomokazu Tamura
    •  & Hiroshi Kida
  7. The Scripps Research Institute, 10550 North Torrey Pines Road, SP-3 La Jolla, California 92037, USA

    • Ryan McBride
    • , Robert P. de Vries
    •  & James C. Paulson
  8. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, Wisconsin 53711, USA

    • Masato Hatta
    • , Hirotaka Imai
    • , Amie J. Eisfeld
    • , Gongxun Zhong
    • , Shufang Fan
    • , Jihui Ping
    • , Eileen A. Maher
    • , Anthony Hanson
    • , Gabriele Neumann
    •  & Yoshihiro Kawaoka
  9. Laboratory of Veterinary Microbiology, Department of Veterinary Sciences, University of Miyazaki, Miyazaki 889-2192, Japan

    • Shinji Watanabe
  10. Influenza and Prion Disease Research Center, National Institute of Animal Health, Kannondai 3-1-5, Tsukuba, Ibaraki 305-0856, Japan

    • Yuko Uchida
    •  & Takehiko Saito
  11. Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan

    • Makoto Ozawa
  12. Transboundary Animal Disease Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan

    • Makoto Ozawa
  13. Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan

    • Hiroshi Kida
  14. Laboratory of Bioresponses Regulation, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan

    • Yoshihiro Kawaoka


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T.W., M.K., S. Fukuyama, M. Imai, S. Yamada, S.M., S. Yamayoshi, K.I.-H., Y. Sakoda, E.T., M.H., S.W., E.A.M., G.N., H.K., T.O., J.C.P., M.T. and Y.K. designed the study; T.W., M.K., S. Fukuyama, N.N., M. Imai, S. Yamada, S.M., S. Yamayoshi, K.I.-H., Y. Sakoda, E.T., R.M., T.N., M.H., H.I., D.Z., N.K., M.S., R.P.d.V., S.S., M. Okamatsu., T.T., Y.T., N.F., K.G., H.K., I.I., M. Ito, Y.S.-T., Y. Sugita, R.U., R.Y., A.J.E., G.Z., S. Fang, J.P., A.H., Y.U., T.S. and H.H. performed the experiments; T.W., M.K., S. Fang, N.N., M. Imai, S. Yamayoshi, S.M., S. Yamada, K.I.-H., Y. Sakoda, E.T., R.M., T.N., M.H., H.I., D.Z., R.P.V., S.S., T.T., Y.T., H.K., E.K. and H. H. analysed the data; T.W., S. Fukuyama, N.N., E.T., R.M., M.H., R.P.d.V., M. Ozawa, G.N., T.O., J.C.P., H.H., M.T. and Y.K. wrote the manuscript; Y.K. oversaw the project. T.W., M.K., S. Fukuyama, N.N. and M. Imai contributed equally to this work.

Competing interests

Y.K. has received speaker’s honoraria from Chugai Pharmaceuticals, Novartis, Daiichi-Sankyo Pharmaceutical, Toyama Chemical, Wyeth, GlaxoSmithKline and Astellas; grant support from Chugai Pharmaceuticals, Daiichi Sankyo Pharmaceutical, Toyama Chemical and Otsuka Pharmaceutical Co.; is a consultant for Crucell; and is a founder of FluGen. G.N. is a founder of FluGen.

Corresponding author

Correspondence to Yoshihiro Kawaoka.

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