Itoh Yasushi, Yoshida Reiko, Shichinohe Shintaro, Higuchi Megumi, Ishigaki Hirohito, Nakayama Misako, Pham Van Loi, Ishida Hideaki, Kitano Mitsutaka, Arikata Masahiko, Kitagawa Naoko, Mitsuishi Yachiyo, Ogasawara Kazumasa, Tsuchiya Hideaki, Hiono Takahiro, Okamatsu Masatoshi, Sakoda Yoshihiro, Kida Hiroshi, Ito Mutsumi, Quynh Mai Le, Kawaoka Yoshihiro, Miyamoto Hiroko, Ishijima Mari, Igarashi Manabu, Suzuki Yasuhiko, Takada Ayato
Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
PLoS Pathog. 2014 Jun 12;10(6):e1004192. doi: 10.1371/journal.ppat.1004192. eCollection 2014 Jun.
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.
H5N1亚型高致病性禽流感（HPAI）病毒常常在人类中引发严重肺炎和多器官衰竭，报告的病例死亡率超过60%。为开发一种临床抗体疗法，我们制备了一种人鼠嵌合单克隆抗体（MAb）ch61，它对从人类分离出的H5N1 HPAI病毒显示出强大的中和活性，并在H5N1 HPAI病毒感染的小鼠和非人灵长类动物模型中评估了其保护潜力。在以致死剂量的病毒进行攻击之前或之后一天用MAb ch61进行被动免疫可完全保护小鼠，而在攻击后3天对小鼠进行治疗则可实现部分保护。在食蟹猴模型中，在攻击后1天和3天静脉注射MAb ch61的食蟹猴中观察到病毒载量降低和对致死性感染的部分保护作用。在免疫抑制的食蟹猴中也注意到了保护作用。尽管从单独用该MAb治疗的食蟹猴中回收了逃避MAb ch61中和作用的突变病毒，但MAb ch61与帕拉米韦联合治疗减少了逃逸突变体的出现。我们的结果表明，在临床病例中，抗体疗法可能有助于降低H5N1 HPAI病毒感染期间的病毒载量并延缓疾病进展，并且与其他抗病毒化合物联合治疗应可提高抗体疗法对H5N1 HPAI病毒感染的保护效果。
