Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses1. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.

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We thank the Centers for Disease Control (CDC) for A/California/04/09 virus and R. Fouchier for A/Netherlands/603/09 virus. We thank K. Wells for editing the manuscript, and M. McGregor, R. Moritz, A. Hanson, H. Ishida, H. Tsuchiya, R. Torii, N. Yamamoto, K. Soda, N. Nomura and H. Yoshida for technical assistance. We also thank T. Umemura, Y. Sunden and T. Tanaka for pathological analyses of virus-infected pigs. This work was supported by National Institute of Allergy and Infectious Diseases Public Health Service research grants, by an NIAID-funded Center for Research on Influenza Pathogenesis (CRIP, HHSN266200700010C), by Grant-in-Aid for Specially Promoted Research, by a contract research fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology, and by grants-in-aid from the Ministry of Health and by ERATO (Japan Science and Technology Agency).

Author Contributions Y.I., K.S., M.K., T.W., Y.S., M.H., Y.M., D.T., Y.S.-T., T.N., M. Imai, S.W., K.I.-H., T.H., N.S., H.K., K.O. and Y.K. designed the experiments; Y.I., K.S., M.K., T.W., Y.S., M.H., D.T., Y.S.-T., T.N., S.S., M. Imai, Y.H., S.W., C.L., S.Y., K.F., S.M., H. Imai, S.K., M. Ito, R.T., K.I.-H., M.S., T.H., Kei Takahashi, A.M., H. Ishigaki, M. Nakayama, M. Okamatsu, Kazuo Takahashi, D.W., P.A.S., R.S., H.S., Y.F., M. Yamashita, K.M., K.N., M. Nakamura, R.B.-S., J.G., H.M. and M. Yamazaki performed the experiments; Y.I., K.S., M.K., T.W., Y.S., M.H., Y.M., Y.S.-T., T.N., M. Imai, S.W., C.L., S.Y., K.I.-H., T.H., H.G., M.S., M. Ozawa, G.N., H.K., K.O. and Y.K. analysed data; Y.I., K.S., M.K., T.W., Y.S., M.H., Y.M., Y.S.-T., T.N., M. Imai, K.I.-H., M.S., M. Ozawa, G.N., K.O. and Y.K. wrote the manuscript. Y.I., K.S., M.K., T.W., Y.S., M.H. and Y.M. contributed equally to this work.

Author information


  1. Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan

    • Yasushi Itoh
    • , Hirohito Ishigaki
    • , Misako Nakayama
    •  & Kazumasa Ogasawara
  2. Department of Microbiology and Infectious Diseases, Kobe University, Hyogo 650-0017, Japan

    • Kyoko Shinya
    • , Akiko Makino
    •  & Yoshihiro Kawaoka
  3. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

    • Maki Kiso
    • , Daisuke Tamura
    • , Yuko Sakai-Tagawa
    • , Saori Sakabe
    • , Shinya Yamada
    • , Ken Fujii
    • , Shin Murakami
    • , Hirotaka Imai
    • , Satoshi Kakugawa
    • , Mutsumi Ito
    • , Ryo Takano
    • , Kiyoko Iwatsuki-Horimoto
    • , Masayuki Shimojima
    • , Taisuke Horimoto
    • , Hideo Goto
    • , Kei Takahashi
    •  & Yoshihiro Kawaoka
  4. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA

    • Tokiko Watanabe
    • , Masato Hatta
    • , Masaki Imai
    • , Yasuko Hatta
    • , Shinji Watanabe
    • , Chengjun Li
    • , M. Suresh
    • , Makoto Ozawa
    • , Gabriele Neumann
    •  & Yoshihiro Kawaoka
  5. Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan

    • Yoshihiro Sakoda
    • , Masatoshi Okamatsu
    •  & Hiroshi Kida
  6. ERATO Infection-Induced Host Responses Project, Saitama 332-0012, Japan

    • Yukiko Muramoto
    •  & Yoshihiro Kawaoka
  7. Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

    • Takeshi Noda
    • , Makoto Ozawa
    •  & Yoshihiro Kawaoka
  8. Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka 537-0025, Japan

    • Kazuo Takahashi
  9. Wisconsin State Laboratory of Hygiene, Madison, Wisconsin 53706, USA

    • David Warshauer
    •  & Peter A. Shult
  10. Department of Public Health, Niigata University, Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan

    • Reiko Saito
    •  & Hiroshi Suzuki
  11. Toyama Chemical Co., Ltd., Toyama 930-8508, Japan

    • Yousuke Furuta
  12. Daiichi Sankyo Co Ltd, Shinagawa, Tokyo 140–8710, Japan

    • Makoto Yamashita
  13. Eiju General Hospital, Tokyo 110-8654, Japan

    • Keiko Mitamura
    • , Kunio Nakano
    •  & Morio Nakamura
  14. School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA

    • Rebecca Brockman-Schneider
    •  & James Gern
  15. Department of Internal Medicine, Mitamura Clinic, Shizuoka 413-0103, Japan

    • Hiroshi Mitamura
  16. Department of Pediatrics, Zama Children’s Clinic, Kanagawa 228-0023, Japan

    • Masahiko Yamazaki
  17. Keiyu Hospital, Kanagawa 220-0012, Japan

    • Norio Sugaya
  18. Creative Research Initiative, Sousei, Hokkaido University, Sapporo 060-0818, Japan

    • Yoshihiro Kawaoka


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Competing interests

[Competing Interests: Y. Kawaoka has received speaker’s honoraria from Chugai Pharmaceuticals, Novartis, Daiichi-Sankyo, Toyama Chemical, Wyeth and GlaxoSmithKline; grant support from Chugai Pharmaceuticals, Daiichi Sankyo Pharmaceutical and Toyama Chemical; consulting fees from Theraclone Sciences, Crucell and Fort Dodge Animal Health; and is a founder of FluGen. G. Neumann has received consulting fees from Theraclone Sciences and is a founder of FluGen. N. Sugaya has received speaker’s honoraria from GlaxoSmithKline, Daiichi Sankyo Pharmaceutical and Tanabe Mitsubishi Pharmaceutical; consulting fees from Daiichi Sankyo Pharmaceutical; and travel support from Denka Seiken. K. Mitamura has received speaker’s honoraria from Chugai Pharmaceuticals and GlaxoSmithCline. G. Neumann is named as co-inventor on several patents about influenza virus reverse genetics and/or the development of influenza virus vaccines or antivirals. Y. Kawaoka is named as inventor/co-inventor on several patents about influenza virus reverse genetics and/or the development of influenza virus vaccines or antivirals.]

Corresponding author

Correspondence to Yoshihiro Kawaoka.

The authors declare competing financial interests: details accompany the full-text HTML version of the paper at www.nature.com/nature.

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