Document text
Principal Investigator: Michel C Nussenzweig
Organization: ROCKEFELLER UNIVERSITY
Fiscal Year: 2020
Award: $400,050
Funding agency: National Institute of Allergy and Infectious Diseases
The WHO and US authorities have declared a public health emergency over the recent outbreak of a new
coronavirus (CoV) originating from Wuhan, China (nCoV-2019, recently renamed SARS-CoV-2 and
responsible for causing the coronavirus disease termed COVID-2019). The discovery of human monoclonal
antibodies to this new CoV and obtaining a molecular understanding of its target epitopes will advance the
development of diagnostics, therapeutics and vaccines to limit virus spread.
The overall goal of this proposal is to discover and characterize potent broadly neutralizing antibodies
to nCoV-2019 that also neutralize closely related strains of CoV such as SARS and other variants currently
found in bats but likely to be able to produce human infections in the future. The Nussenzweig laboratory
has developed robust methods to isolate, recombinantly produce and characterize human antibodies from
the memory B cells of individuals infected by a series of different pathogens including HIV-1, Flaviviruses
including Zika, and Hepatitis B virus (1, 2). These methods have also been used by other laboratories to
isolate neutralizing antibodies to malaria, Ebola, influenza and other human infections (reviewed in (3)). The
Bjorkman laboratory has performed structural studies using these antibodies to obtain information that directs
vaccine design and therapies (2, 4-23).
In Aim 1, we obtain samples from nCoV-2019 convalescing individuals (see letter from Dr. Wesley
Van Voorhis). Serum samples will be tested for binding to the trimeric nCoV-2019 spike protein (S) and to the
isolated receptor binding domain (RBD) of the S protein (see letter of collaboration from Dr. John Pak at Chan-
Zuckerberg Biohub). Individuals with high titers against S and RBD will be recruited for large blood donations.
Antibodies will be identified from the memory B cells of these individuals. In Aim 2 we will clone and express
the antibodies obtained in Aim 1. The anti-nCoV-2019 antibodies will be tested for binding to the S protein
from Severe Acute Respiratory Syndrome (SARS) and other closely related bat-derived CoV to test for cross-
reactivity. Any promising antibodies will be evaluated for neutralizing activity (see letter by Dr. Timothy
Sheahan at the University of North Carolina). In Aim 3 Dr. Bjorkman will solve crystal structures of antibody
Fabs, and cryo-EM structures of coronavirus spike trimers complexed with Fabs from antibodies identified
from Aims 1 and 2.
In addition to helping guide vaccine development through the identification of neutralizing targets, the
proposed discovery of human monoclonal antibodies to nCoV-2019 and related viruses bears a significant
translational potential, such as the treatment and prophylaxis of severe medical conditions associated with
nCoV-2019 infection by passive antibody transfer.
Terms: <2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Advanced Development><Antibodies><Antigenic Determinants><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bats><Bears><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><Blood><Blood Donations><Blood Reticuloendothelial System><Blood Serum><COVID><Cell Body><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Surface Antigens><Cells><China><Chiroptera><Cloning><CoV S protein><CoV disease><CoV emergence><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><Collaborations><Complex><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Cryo-electron Microscopy><Cryoelectron Microscopy><Crystallization><Development><Diagnostic><Disease><Disease Outbreaks><Disorder><ELISA><Ebola><Electron Cryomicroscopy><Enzyme-Linked Immunosorbent Assay><Epitopes><Flavivirus><Future><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grippe><Group B Arbovirus><HBV><HIV><HIV-1><HIV-I><HIV1><Health><Hepatitis B Virus><Homologous Serum Hepatitis Virus><Hu-mABs><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><IgG><Immunoglobulin G><Immunologic Surface Markers><Immunological Surface Markers><In Vitro><Individual><Infection><Influenza><Knowledge><LAV-HTLV-III><Laboratories><Letters><Light><Lymphadenopathy-Associated Virus><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Mainland China><Malaria><Medical><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Memory B Cell><Memory B-Lymphocyte><Methods><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutation><North Carolina><Outbreaks><Paludism><Passive Antibody Transfers><Passive Transfer of Immunity><Patients><Photoradiation><Plasmodium Infections><Pre-Clinical Model><Preclinical Models><Procedures><Prophylactic treatment><Prophylaxis><Protein Binding Domain><Protein Binding Motif><Protein-Protein Interaction Domain><Proteins><Protomer><Recombinants><Resistance><SARS><SARS coronavirus disease><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Sampling><Series><Serum><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Structure><Surface Antigens><Surface Proteins><Techniques><Testing><Therapeutic><Transfection><Universities><Ursidae><Ursidae Family><VAC-TX><Vaccine Design><Vaccine Therapy><Vaccines><Variant><Variation><Virus><Virus-HIV><Washington><Wuhan coronavirus><ZIKA><authority><bear><cell sorting><conformation><conformational state><corona virus><corona virus disease><coronavirus S protein><coronavirus disease><coronavirus emergence><coronavirus spike glycoprotein><cross reactivity><cryo-EM><cryoEM><develop a vaccine><development of a vaccine><developmental><effective therapy><effective treatment><emergent CoV><emergent coronavirus><emerging CoV><emerging coronavirus><experiment><experimental research><experimental study><expression vector><flu infection><genome mutation><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><in vitro activity><in vivo><influenza infection><medical countermeasure><nCoV><neutralizing antibody><new CoV><new coronavirus><novel CoV><novel coronavirus><particle><pathogen><prevent><preventing><protein complex><protein structure><protein structures><proteins structure><public health emergency><receptor binding><receptor bound><recruit><resistant><therapeutic vaccination><vaccine development><vaccine formulation>