Nature 460, 1021-1025 (20 August 2009) | doi:10.1038/nature08260; Received 2 June 2009; Accepted 3 July 2009; Published online 13 July 2009

In vitro and in vivo characterization of new swine-origin H1N1 influenza virusesnear-final version

Yasushi Itoh1, Kyoko Shinya2, Maki Kiso3, Tokiko Watanabe4, Yoshihiro Sakoda5, Masato Hatta4, Yukiko Muramoto6, Daisuke Tamura3, Yuko Sakai-Tagawa3, Takeshi Noda7, Saori Sakabe3, Masaki Imai4, Yasuko Hatta4, Shinji Watanabe4, Chengjun Li4, Shinya Yamada3, Ken Fujii3, Shin Murakami3, Hirotaka Imai3, Satoshi Kakugawa3, Mutsumi Ito3, Ryo Takano3, Kiyoko Iwatsuki-Horimoto3, Masayuki Shimojima3, Taisuke Horimoto3, Hideo Goto3, Kei Takahashi3, Akiko Makino2, Hirohito Ishigaki1, Misako Nakayama1, Masatoshi Okamatsu5, Kazuo Takahashi8, David Warshauer9, Peter A. Shult9, Reiko Saito10, Hiroshi Suzuki10, Yousuke Furuta11, Makoto Yamashita12, Keiko Mitamura13, Kunio Nakano13, Morio Nakamura13, Rebecca Brockman-Schneider14, Hiroshi Mitamura15, Masahiko Yamazaki16, Norio Sugaya17, M. Suresh4, Makoto Ozawa4,7, Gabriele Neumann4, James Gern14, Hiroshi Kida5, Kazumasa Ogasawara1 & Yoshihiro Kawaoka2,3,4,6,7,18

  1. Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan
  2. Department of Microbiology and Infectious Diseases, Kobe University, Hyogo 650-0017, Japan
  3. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
  4. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA
  5. Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
  6. ERATO Infection-Induced Host Responses Project, Saitama 332-0012, Japan
  7. Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
  8. Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka 537-0025, Japan
  9. Wisconsin State Laboratory of Hygiene, Madison, Wisconsin 53706, USA
  10. Department of Public Health, Niigata University, Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
  11. Toyama Chemical Co., Ltd., Toyama 930-8508, Japan
  12. Daiichi Sankyo Co Ltd, Shinagawa, Tokyo 140–8710, Japan
  13. Eiju General Hospital, Tokyo 110-8654, Japan
  14. School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA
  15. Department of Internal Medicine, Mitamura Clinic, Shizuoka 413-0103, Japan
  16. Department of Pediatrics, Zama Children's Clinic, Kanagawa 228-0023, Japan
  17. Keiyu Hospital, Kanagawa 220-0012, Japan
  18. Creative Research Initiative, Sousei, Hokkaido University, Sapporo 060-0818, Japan

Correspondence to: Yoshihiro Kawaoka2,3,4,6,7,18 Correspondence and requests for materials should be addressed to Y.K. (Email: kawaokay@svm.vetmed.wisc.edu).

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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