Human Antibodies Targeting Influenza B Virus Neuraminidase Active Site Are Broadly Protective
Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target...
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Published in | Immunity (Cambridge, Mass.) Vol. 53; no. 4; pp. 852 - 863.e7 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
Elsevier Inc
13.10.2020
Elsevier Limited |
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Abstract | Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved among IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs.
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•Generation of seven human monoclonal antibodies to influenza B virus neuraminidase•Two antibodies, 1G05 and 2E01, are broadly cross-reactive•1G05 and 2E01 are potently protective against lethal Influenza B infection in mice•1G05 and 2E01 bind conserved residues in the Influenza B neuraminidase active site
Influenza B virus (IBV) infections cause severe disease. Madsen et al. develop and characterize human monoclonal antibodies that possess broad and potent capacities to inhibit IBV neuraminidase enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. |
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AbstractList | Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved among IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs.Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved among IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs. Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved among IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs. [Display omitted] •Generation of seven human monoclonal antibodies to influenza B virus neuraminidase•Two antibodies, 1G05 and 2E01, are broadly cross-reactive•1G05 and 2E01 are potently protective against lethal Influenza B infection in mice•1G05 and 2E01 bind conserved residues in the Influenza B neuraminidase active site Influenza B virus (IBV) infections cause severe disease. Madsen et al. develop and characterize human monoclonal antibodies that possess broad and potent capacities to inhibit IBV neuraminidase enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved among IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs. SummaryInfluenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved among IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs. Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro , and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved amongst IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs. Influenza B virus (IBV) infections cause severe disease. Madsen et al. develop and characterize human monoclonal antibodies that possess broad and potent capacities to inhibit IBV neuraminidase enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. |
Author | Krammer, Florian Ellebedy, Ali H. Cox, Rebecca J. Alsoussi, Wafaa B. Tan, Jessica Madsen, Anders Mudd, Philip A. Strohmeier, Shirin Schmitz, Aaron J. Amor, Mostafa Mohammed, Bassem M. Simon, Viviana Fremont, Daved H. Dai, Ya-Nan McMahon, Meagan Lei, Tingting Turner, Jackson S. |
AuthorAffiliation | 10 Lead contact 6 Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA 5 Department of Microbiology, Haukeland University Hospital, 5021 Bergen, Norway 9 Equal contribution 3 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 8 The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA 1 Influenza Centre, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway 4 Division of Emergency Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA 7 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA |
AuthorAffiliation_xml | – name: 4 Division of Emergency Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA – name: 9 Equal contribution – name: 8 The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA – name: 1 Influenza Centre, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway – name: 3 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – name: 10 Lead contact – name: 6 Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA – name: 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – name: 5 Department of Microbiology, Haukeland University Hospital, 5021 Bergen, Norway – name: 7 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA |
Author_xml | – sequence: 1 givenname: Anders orcidid: 0000-0002-0626-5443 surname: Madsen fullname: Madsen, Anders organization: Influenza Centre, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway – sequence: 2 givenname: Ya-Nan orcidid: 0000-0003-1618-3043 surname: Dai fullname: Dai, Ya-Nan organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 3 givenname: Meagan surname: McMahon fullname: McMahon, Meagan organization: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – sequence: 4 givenname: Aaron J. surname: Schmitz fullname: Schmitz, Aaron J. organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 5 givenname: Jackson S. surname: Turner fullname: Turner, Jackson S. organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 6 givenname: Jessica surname: Tan fullname: Tan, Jessica organization: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – sequence: 7 givenname: Tingting surname: Lei fullname: Lei, Tingting organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 8 givenname: Wafaa B. surname: Alsoussi fullname: Alsoussi, Wafaa B. organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 9 givenname: Shirin surname: Strohmeier fullname: Strohmeier, Shirin organization: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – sequence: 10 givenname: Mostafa surname: Amor fullname: Amor, Mostafa organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 11 givenname: Bassem M. surname: Mohammed fullname: Mohammed, Bassem M. organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 12 givenname: Philip A. orcidid: 0000-0002-3860-5473 surname: Mudd fullname: Mudd, Philip A. organization: Division of Emergency Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 13 givenname: Viviana surname: Simon fullname: Simon, Viviana organization: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – sequence: 14 givenname: Rebecca J. surname: Cox fullname: Cox, Rebecca J. organization: Influenza Centre, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway – sequence: 15 givenname: Daved H. surname: Fremont fullname: Fremont, Daved H. email: fremont@wustl.edu organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 16 givenname: Florian surname: Krammer fullname: Krammer, Florian email: florian.krammer@mssm.edu organization: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – sequence: 17 givenname: Ali H. surname: Ellebedy fullname: Ellebedy, Ali H. email: ellebedy@wustl.edu organization: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA |
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Keywords | Human Infection Plasmablasts Neuraminidase Monoclonal antibodies Influenza B virus B cells |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 A.M., Y.D., M.M., A.J.S., J.T., T.L., W.A.B., S.S., M.A., B.M.M., and V.S. characterized the antibodies; A.J.S., J.S.T., and P.A.M. isolated the antibodies; and A.M., Y.D., R.J.C., D.H.F., F.K., and A.H.E. conceptualized the study and wrote the manuscript. AUTHOR CONTRIBUTIONS |
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Snippet | Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV... SummaryInfluenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness... |
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Title | Human Antibodies Targeting Influenza B Virus Neuraminidase Active Site Are Broadly Protective |
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