Date Published: June 12, 2014
Publisher: Public Library of Science
Author(s): Yasushi Itoh, Reiko Yoshida, Shintaro Shichinohe, Megumi Higuchi, Hirohito Ishigaki, Misako Nakayama, Van Loi Pham, Hideaki Ishida, Mitsutaka Kitano, Masahiko Arikata, Naoko Kitagawa, Yachiyo Mitsuishi, Kazumasa Ogasawara, Hideaki Tsuchiya, Takahiro Hiono, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida, Mutsumi Ito, Le Quynh Mai, Yoshihiro Kawaoka, Hiroko Miyamoto, Mari Ishijima, Manabu Igarashi, Yasuhiko Suzuki, Ayato Takada, Andrew Pekosz.
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.
Influenza A viruses are divided into subtypes based on the antigenicity of two envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). To date, H1-H16 HA and N1-N9 NA subtypes have been found in wild aquatic birds, the natural reservoir of influenza viruses –. Of these HA subtypes, only some avian influenza viruses of the H5 and H7 subtypes are known to become highly pathogenic avian influenza (HPAI) viruses under natural conditions. While HPAI viruses cause an acute systemic disease in poultry with a mortality rate that often approaches 100%, avian to human transmission of HPAI viruses is limited and HPAI viruses had never been reported to cause lethal infection in humans until the first emergence of an H5N1 HPAI virus in southern China in 1996.
Current strategies for the control of influenza include vaccination and antiviral drug treatment. Neuraminidase inhibitors have been used for H5N1 HPAI virus infection in humans as well as seasonal influenza caused by viruses of the H1 and H3 HA subtypes. However, the efficacy of the neuraminidase inhibitors on the human H5N1 infections is unclear due to the inevitable lack of adequate control studies. Moreover, drug-resistant H5N1 viruses were indeed detected in patients ,  and, importantly, H5N1 viruses with reduced sensitivity to neuraminidase inhibitors were also isolated from chickens in the endemic area . Thus, alternative strategies for prophylaxis and treatment need to be developed for pandemic preparedness against the H5N1 influenza virus.