title: A Broadly Reactive Human Anti-hemagglutinin Stem Monoclonal Antibody That Inhibits Influenza A Virus Particle Release.
abstract: Many broadly reactive human monoclonal antibodies against the hemagglutinin (HA) stem of influenza A virus have been developed for therapeutic applications. These antibodies typically inhibit viral entry steps, especially the HA conformational change that is required for membrane fusion. To better understand the mechanisms by which such antibodies inhibit viral replication, we established broadly reactive human anti-HA stem antibodies and determined the properties of these antibodies by examining their reactivity with 18 subtypes of HA, evaluating their in vivo protective efficacy, identifying their epitopes, and characterizing their inhibitory mechanisms. Among the eight human monoclonal antibodies we generated, which recognized at least 3 subtypes of the soluble HA antigens tested, clone S9-1-10/5-1 reacted with 18 subtypes of HA and protected mice from lethal infection with H1N1pdm09, H3N2, H5N1, and H7N9 viruses. This antibody recognized the HA2 helix A in the HA stem, and inhibited virus particle release from infected cells but did not block viral entry completely. These results show that broadly reactive human anti-HA stem antibodies can exhibit protective efficacy by inhibiting virus particle release. These findings expand our knowledge of the mechanisms by which broadly reactive stem-targeting antibodies inhibit viral replication and provide valuable information for universal vaccine development.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Yamayoshi
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Uraki
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Ito
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kiso
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Sumiho
authors.initials: S
authors.lastname: Nakatsu
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Yasuhara
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Oishi
authors.affiliation: Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ikuta
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, USA; Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Japan; ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Japan. Electronic address: yoshihiro.kawaoka@wisc.edu.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000915:Antibody Affinity; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D000939:Epitopes / Q000276:immunology; D057809:HEK293 Cells; D006367:HeLa Cells; D006388:Hemagglutinins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology / Q000502:physiology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D057074:Virus Release; D014779:Virus Replication
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D006388:Hemagglutinins
keywords: Broadly reactive; HA stem; Human monoclonal antibody; Influenza A virus