Instructions for use Title Protective Efficacy of Passive Immunization with Monoclonal Antibodies in Animal Models of H 5 N 1 HighlyPathogenic Avian Influenza Virus Infection

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. Citation: Itoh Y, Yoshida R, Shichinohe S, Higuchi M, Ishigaki H, et al. (2014) Protective Efficacy of Passive Immunization with Monoclonal Antibodies in Animal Models of H5N1 Highly Pathogenic Avian Influenza Virus Infection. PLoS Pathog 10(6): e1004192. doi:10.1371/journal.ppat. 1004192 Editor: Andrew Pekosz, Johns Hopkins University Bloomberg School of Public Health, United States of America Received December 25, 2013; Accepted May 2, 2014; Published June 12, 2014 Copyright: 2014 Itoh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Japan Science and Technology Agency Basic Research (http://www.jsps.go.jp/english/index.html), and partly by the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) (http://www.crnid.riken.jp/jgrid/en/) and the Global COE Program (http://www.jsps.go.jp/ english/index.html) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT, http://www.mext.go.jp/english/), Japan, and Grant-in-Aid for Scientific Research (B) JSPS KAKENHI Grant number 22390076. Funding was also provided partly by the Japan Science and Technology Agency (JST) and Japan International Cooperation Agency (JICA) within the framework of the Science and Technology Research Partnership for Sustainable Development (SATREPS) (http://www.jst.go.jp/global/english/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: MK is employed by Shionogi & Co., Ltd., a company developing the neuraminidase inhibitor used in this study. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials. * E-mail: atakada@czc.hokudai. ac.jp . These authors contributed equally to this work.