title: Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins.
abstract: The pandemic threat posed by emerging zoonotic influenza A viruses necessitates development of antiviral agents effective against various antigenic subtypes. Human monoclonal antibody (hMAb) targeting the hemagglutinin (HA) stalk offers a promising approach to control influenza virus infections. Here, we investigated the ability of the hMAb 81.39a to inhibit in vitro replication of human and zoonotic viruses, representing 16 HA subtypes. The majority of viruses were effectively neutralized by 81.39a at a 50% effective concentration (EC50) of <0.01 to 4.9 μg/ml. Among group 2 HA viruses tested, a single A(H7N9) virus was not neutralized at 50 μg/ml; it contained HA2-Asp19Gly, an amino acid position previously associated with resistance to neutralization by the group 2 HA-neutralizing MAb CR8020. Notably, among group 1 HA viruses, H11-H13 and H16 subtypes were not neutralized at 50 μg/ml; they shared the substitution HA2-Asp19Asn/Ala. Conversely, H9 viruses harboring HA2-Asp19Ala were fully susceptible to neutralization. Therefore, amino acid variance at HA2-Asp19 has subtype-specific adverse effects on in vitro neutralization. Mice given a single injection (15 or 45 mg/kg of body weight) at 24 or 48 h after infection with recently emerged A(H5N2), A(H5N8), A(H6N1), or A(H7N9) viruses were protected from mortality and showed drastically reduced lung viral titers. Furthermore, 81.39a protected mice infected with A(H7N9) harboring HA2-Asp19Gly, although the antiviral effect was lessened. A(H1N1)pdm09-infected ferrets receiving a single dose (25 mg/kg) had reduced viral titers and showed less lung tissue injury, despite 24- to 72-h-delayed treatment. Taken together, this study provides experimental evidence for the therapeutic potential of 81.39a against diverse influenza A viruses.
  
  
  OBJECTIVE
  Zoonotic influenza viruses, such as A(H5N1) and A(H7N9) subtypes, have caused severe disease and deaths in humans, raising public health concerns. Development of novel anti-influenza therapeutics with a broad spectrum of activity against various subtypes is necessary to mitigate disease severity. Here, we demonstrate that the hemagglutinin (HA) stalk-targeting human monoclonal antibody 81.39a effectively neutralized the majority of influenza A viruses tested, representing 16 HA subtypes. Furthermore, delayed treatment with 81.39a significantly suppressed virus replication in the lungs, prevented dramatic body weight loss, and increased survival rates of mice infected with A(H5Nx), A(H6N1), or A(H7N9) viruses. When tested in ferrets, delayed 81.39a treatment reduced viral titers, particularly in the lower respiratory tract, and substantially alleviated disease symptoms associated with severe A(H1N1)pdm09 influenza. Collectively, our data demonstrated the effectiveness of 81.39a against both seasonal and emerging influenza A viruses.
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Henju
authors.initials: H
authors.lastname: Marjuki
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Vasiliy P
authors.initials: VP
authors.lastname: Mishin
authors.affiliation: Infectious Diseases, Genentech Inc., South San Francisco, California, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Chai
authors.affiliation: Infectious Diseases, Genentech Inc., South San Francisco, California, USA.
authors.forename: Man-Wah
authors.initials: MW
authors.lastname: Tan
authors.affiliation: Portfolio Management and Operations Departments, Genentech Inc., South San Francisco, California, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Newton
authors.affiliation: Influenza Division, Biomedical Advanced Research and Development Authority, Washington, DC, USA.
authors.forename: John
authors.initials: J
authors.lastname: Tegeris
authors.affiliation: Influenza Division, Biomedical Advanced Research and Development Authority, Washington, DC, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Erlandson
authors.affiliation: Influenza Division, Biomedical Advanced Research and Development Authority, Washington, DC, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Willis
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Jones
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Davis
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: James
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA lgubareva@cdc.gov.
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Gubareva
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000627:therapeutic use; D000914:Antibodies, Viral / Q000276:immunology* / Q000627:therapeutic use; D000940:Antigenic Variation / Q000235:genetics / Q000276:immunology; D005260:Female; D005289:Ferrets; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D009980:Influenza A virus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000821:virology; D008168:Lung / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000628:therapy / Q000821:virology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus