title: 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.
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Yoshida
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Shichinohe
authors.affiliation: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Ishigaki
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Van Loi
authors.initials: VL
authors.lastname: Pham
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan; Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Kitano
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Arikata
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kitagawa
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Yachiyo
authors.initials: Y
authors.lastname: Mitsuishi
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ogasawara
authors.affiliation: Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tsuchiya
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hiono
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Okamatsu
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sakoda
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Ito
authors.affiliation: National Institute of Hygiene and Epidemiology, Hanoi, Vietnam.
authors.forename: Le
authors.initials: L
authors.lastname: Quynh Mai
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.affiliation: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Miyamoto
authors.affiliation: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ishijima
authors.affiliation: Division of Bioinformatics, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors.forename: Ayato
authors.initials: A
authors.lastname: Takada
mesh_terms: D000146:Acids, Carbocyclic; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000627:therapeutic use; D002460:Cell Line; D003517:Cyclopentanes / Q000627:therapeutic use; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D006146:Guanidines / Q000627:therapeutic use; D007116:Immunization, Passive / Q000379:methods*; D016867:Immunocompromised Host / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology* / Q000302:isolation & purification; D015850:Interleukin-6 / Q000097:blood; D008168:Lung / Q000473:pathology / Q000821:virology; D008252:Macaca fascicularis; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019562:Viral Load / Q000276:immunology
chemical_list: D000146:Acids, Carbocyclic; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D003517:Cyclopentanes; D006146:Guanidines; D015850:Interleukin-6; D009439:Neuraminidase; C414210:peramivir