Influenza H7N9 Virus Neuraminidase-Specific Human Monoclonal Antibodies Inhibit Viral Egress and Protect from Lethal Influenza Infection in Mice
H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined....
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Published in | Cell host & microbe Vol. 26; no. 6; pp. 715 - 728.e8 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
11.12.2019
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Subjects | |
Online Access | Get full text |
ISSN | 1931-3128 1934-6069 1934-6069 |
DOI | 10.1016/j.chom.2019.10.003 |
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Abstract | H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection in vivo in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection.
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•Human mAbs recognize several antigenic sites on influenza virus N9 NA•The mAbs act by blocking egress of nascent virions from infected cells•Human mAbs mediate prophylactic and therapeutic protection in vivo in mice•Protection is mediated by direct virus neutralization or Fc-region effector function
Molecular determinants of the human B cell response to avian influenza N9 neuraminidase (NA) proteins, which differ from seasonal virus NAs, are ill-defined. Gilchuk et al. identify antibodies to multiple protective antigenic sites on N9 NA that block egress of nascent virions from infected cells and mediate protection in mice. |
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AbstractList | H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection
in vivo
in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection.
Molecular determinants of the human B cell response to avian influenza N9 neuraminidase (NA) proteins, which differ from seasonal virus NAs, are ill-defined. Gilchuk et al. identify antibodies to multiple protective antigenic sites on N9 NA that block egress of nascent virions from infected cells and mediate protection in mice. H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection in vivo in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection.H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection in vivo in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection. H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection in vivo in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection. H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection in vivo in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection. [Display omitted] •Human mAbs recognize several antigenic sites on influenza virus N9 NA•The mAbs act by blocking egress of nascent virions from infected cells•Human mAbs mediate prophylactic and therapeutic protection in vivo in mice•Protection is mediated by direct virus neutralization or Fc-region effector function Molecular determinants of the human B cell response to avian influenza N9 neuraminidase (NA) proteins, which differ from seasonal virus NAs, are ill-defined. Gilchuk et al. identify antibodies to multiple protective antigenic sites on N9 NA that block egress of nascent virions from infected cells and mediate protection in mice. |
Author | Bombardi, Robin G. Wilson, Ian A. Li, Sheng Bangaru, Sandhya Creech, C. Buddy Turner, Hannah L. Gilchuk, Iuliia M. Edwards, Kathryn M. Gilchuk, Pavlo Irving, Ryan P. Kose, Nurgun Crowe, James E. Zhu, Xueyong Yu, Wenli Ward, Andrew B. Thornburg, Natalie J. |
AuthorAffiliation | 1 The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA 5 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA 7 These authors contributed equally 3 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA 8 Lead Contact 6 Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA 4 Department of Medicine, School of Medicine, University of California, San Diego, San Diego, CA 92093, USA 2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA |
AuthorAffiliation_xml | – name: 3 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA – name: 6 Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA – name: 7 These authors contributed equally – name: 1 The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA – name: 4 Department of Medicine, School of Medicine, University of California, San Diego, San Diego, CA 92093, USA – name: 2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA – name: 5 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA – name: 8 Lead Contact |
Author_xml | – sequence: 1 givenname: Iuliia M. surname: Gilchuk fullname: Gilchuk, Iuliia M. organization: The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 2 givenname: Sandhya surname: Bangaru fullname: Bangaru, Sandhya organization: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 3 givenname: Pavlo surname: Gilchuk fullname: Gilchuk, Pavlo organization: The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 4 givenname: Ryan P. surname: Irving fullname: Irving, Ryan P. organization: The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 5 givenname: Nurgun surname: Kose fullname: Kose, Nurgun organization: The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 6 givenname: Robin G. surname: Bombardi fullname: Bombardi, Robin G. organization: The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 7 givenname: Natalie J. surname: Thornburg fullname: Thornburg, Natalie J. organization: The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 8 givenname: C. Buddy surname: Creech fullname: Creech, C. Buddy organization: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 9 givenname: Kathryn M. surname: Edwards fullname: Edwards, Kathryn M. organization: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA – sequence: 10 givenname: Sheng surname: Li fullname: Li, Sheng organization: Department of Medicine, School of Medicine, University of California, San Diego, San Diego, CA 92093, USA – sequence: 11 givenname: Hannah L. surname: Turner fullname: Turner, Hannah L. organization: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA – sequence: 12 givenname: Wenli surname: Yu fullname: Yu, Wenli organization: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA – sequence: 13 givenname: Xueyong surname: Zhu fullname: Zhu, Xueyong organization: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA – sequence: 14 givenname: Ian A. surname: Wilson fullname: Wilson, Ian A. organization: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA – sequence: 15 givenname: Andrew B. surname: Ward fullname: Ward, Andrew B. organization: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA – sequence: 16 givenname: James E. surname: Crowe fullname: Crowe, James E. email: james.crowe@vumc.org organization: The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA |
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Keywords | epitopes pre-exposure prophylaxis neuraminidase B lymphocyte antibodies monoclonal H7N9 influenza A virus |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS X.Z. and W.Y. produced N9, N6, and N7 NA proteins. S.B., N.K., N.J.T., and I.M.G. performed initial screening and isolation of antibodies and isolated hybridomas. R.G.B. sequenced antibody clones and produced synthetic DNA in expression vectors. S.B. purified antibodies. S.B. and I.M.G. performed ELISA and ELLA NI; I.M.G. conducted egress assays and NA-Fluor NI assays and performed HAI. S.L. performed HDX-MS experiments. B.C. and K.M.E. directed the sample collection. H.L.T. and A.B.W. performed nsEM studies. I.M.G., P.G., and R.I. performed animal protection studies. S.B., I.M.G., and J.E.C. wrote the first draft of the manuscript. All authors revised and approved the final version of the manuscript. |
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SubjectTerms | Animals antibodies Antibodies, Heterophile - pharmacology Antibodies, Monoclonal - pharmacology Antibodies, Neutralizing - pharmacology Antibodies, Viral - pharmacology B lymphocyte Birds epitopes Epitopes - immunology H7N9 Humans influenza A virus Influenza A Virus, H7N9 Subtype - drug effects Influenza A Virus, H7N9 Subtype - immunology Influenza in Birds - prevention & control Influenza in Birds - virology Influenza Vaccines - immunology Influenza, Human - prevention & control Influenza, Human - virology Mice monoclonal neuraminidase Neuraminidase - immunology Orthomyxoviridae Infections - prevention & control Orthomyxoviridae Infections - virology Pre-Exposure Prophylaxis Vaccination Vaccines, Inactivated Viral Proteins - immunology Virus Release - drug effects |
Title | Influenza H7N9 Virus Neuraminidase-Specific Human Monoclonal Antibodies Inhibit Viral Egress and Protect from Lethal Influenza Infection in Mice |
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