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

Abstract

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.

Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates

“…Although the H7N9 vaccine in the present study conferred sufficient protective immunity to prevent severe viral pneumonia with virus inoculation through the trachea, we need to pay attention to the emergence and containment of resistant viruses during treatment with NA inhibitors even in immunocompetent patients, as confirmed in the present study using healthy macaques. Furthermore, development of antiviral drugs with an alternative mode of action and combinational therapy using those drugs might be required for treatment of H7N9 virus infection (11,61) in addition to research of host factors that allow the emergence of resistant viruses in primates.…”

Efficacy of Repeated Intravenous Administration of Peramivir against Highly Pathogenic Avian Influenza A (H5N1) Virus in Cynomolgus Macaques

“…These results suggest that virus in the lungs in the late phase causes a high body temperature. Therefore, treatment of HPAIV infection with peramivir for more than 5 days might be required for a further reduction of virus propagation and amelioration of symptoms since macaques infected with HPAIV occasionally showed fetal symptoms (22,25,26,35).…”

“…Although mouse and ferret models have provided insight into the pathogenesis of H5N1 HPAIV in mammalian hosts, the pathogenicity in those models cannot be directly extrapolated to humans. In our previous studies, though the mortality rate in cynomolgus macaques due to H5N1 HPAIVs was lower than that in humans, H5N1 HPAIVs induced severe pneumonia and symptoms in cynomolgus macaques, compared with pandemic (H1N1) 2009 virus, as reported in human patients (24)(25)(26). Therefore, the use of cynomolgus macaques enabled not only analysis of the pathogenicity of various influenza viruses but also evaluation of the efficacy of vaccines and antiviral agents (27).…”

A critical analysis of the cynomolgus macaque, Macaca fascicularis, as a model to test HIV-1/SIV vaccine efficacy

“…Cynomolgus macaques are used in kidney transplantation studies [110], evaluation of pharmacological safety [111], bone remodelling and osteoporosis [112], cardiovascular research [113] and viral pathogenesis [114,115]. Most importantly, due to their ready availability, favourable clinical outcomes and immunological profiles for vaccine design, cynomolgus macaques are becoming an increasingly preferred animal model among HIV researchers [6].…”