title: Broadly-Reactive Neutralizing and Non-neutralizing Antibodies Directed against the H7 Influenza Virus Hemagglutinin Reveal Divergent Mechanisms of Protection.
abstract: In the early spring of 2013, Chinese health authorities reported several cases of H7N9 influenza virus infections in humans. Since then the virus has established itself at the human-animal interface in Eastern China and continues to cause several hundred infections annually. In order to characterize the antibody response to the H7N9 virus we generated several mouse monoclonal antibodies against the hemagglutinin of the A/Shanghai/1/13 (H7N9) virus. Of particular note are two monoclonal antibodies, 1B2 and 1H5, that show broad reactivity to divergent H7 hemagglutinins. Monoclonal antibody 1B2 binds to viruses of the Eurasian and North American H7 lineages and monoclonal antibody 1H5 reacts broadly to virus isolates of the Eurasian lineage. Interestingly, 1B2 shows broad hemagglutination inhibiting and neutralizing activity, while 1H5 fails to inhibit hemagglutination and demonstrates no neutralizing activity in vitro. However, both monoclonal antibodies were highly protective in an in vivo passive transfer challenge model in mice, even at low doses. Experiments using mutant antibodies that lack the ability for Fc/Fc-receptor and Fc/complement interactions suggest that the protection provided by mAb 1H5 is, at least in part, mediated by the Fc-fragment of the mAb. These findings highlight that a protective response to a pathogen may not only be due to neutralizing antibodies, but can also be the result of highly efficacious non-neutralizing antibodies not readily detected by classical in vitro neutralization or hemagglutination inhibition assays. This is of interest because H7 influenza virus vaccines induce only low hemagglutination inhibiting antibody titers while eliciting robust antibody titers as measured by ELISA. Our data suggest that these binding but non-neutralizing antibodies contribute to protection in vivo.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Gene S
authors.initials: GS
authors.lastname: Tan
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Leon
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Randy A
authors.initials: RA
authors.lastname: Albrecht
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Margine
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ariana
authors.initials: A
authors.lastname: Hirsh
authors.affiliation: School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Justin
authors.initials: J
authors.lastname: Bahl
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Florian
authors.initials: F
authors.lastname: Krammer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D005434:Flow Cytometry; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype; D007252:Influenza Vaccines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; C109963:hemagglutinin, avian influenza A virus