Protective Efficacy of Passive Immunization with Monoclonal Antibodies in Animal Models of H5N1 Highly Pathogenic Avian Influenza Virus Infection

PLoS Pathogens

Mari Ishijima¹  Yachiyo Mitsuishi²  Mitsutaka Kitano²  Hideaki Ishida²  Van Loi Pham²  Naoko Kitagawa²  Hideaki Tsuchiya²  Hirohito Ishigaki²  Yasushi Itoh²  Misako Nakayama²  Kazumasa Ogasawara²  Ayato Takada³  Yasuhiko Suzuki⁴  Megumi Higuchi⁴  Manabu Igarashi⁴  Reiko Yoshida⁴  Hiroko Miyamoto⁵  Le Quynh Mai⁵  Masahiko Arikata⁶  Shintaro Shichinohe⁷  Yoshihiro Sakoda⁷  Mutsumi Ito⁷  Hiroshi Kida⁷  Masatoshi Okamatsu⁷  Yoshihiro Kawaoka⁸  Takahiro Hiono⁹ 

[1] Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, United States of America;Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan;Division of Bioinformatics, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan;Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan;Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan;Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan;Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan;National Institute of Hygiene and Epidemiology, Hanoi, Vietnam;Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan

关键词: Macaque;    H5N1;    Antibodies;    Mouse models;    Respiratory infections;    Animal models of infection;    Viral pathogens;    Influenza viruses;   

DOI  :  10.1371/journal.ppat.1004192

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype often cause severe pneumonia and multiple organ failure in humans, with reported case fatality rates of more than 60%. To develop a clinical antibody therapy, we generated a human-mouse chimeric monoclonal antibody (MAb) ch61 that showed strong neutralizing activity against H5N1 HPAI viruses isolated from humans and evaluated its protective potential in mouse and nonhuman primate models of H5N1 HPAI virus infections. Passive immunization with MAb ch61 one day before or after challenge with a lethal dose of the virus completely protected mice, and partial protection was achieved when mice were treated 3 days after the challenge. In a cynomolgus macaque model, reduced viral loads and partial protection against lethal infection were observed in macaques treated with MAb ch61 intravenously one and three days after challenge. Protective effects were also noted in macaques under immunosuppression. Though mutant viruses escaping from neutralization by MAb ch61 were recovered from macaques treated with this MAb alone, combined treatment with MAb ch61 and peramivir reduced the emergence of escape mutants. Our results indicate that antibody therapy might be beneficial in reducing viral loads and delaying disease progression during H5N1 HPAI virus infection in clinical cases and combined treatment with other antiviral compounds should improve the protective effects of antibody therapy against H5N1 HPAI virus infection.

【 授权许可】

CC BY