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Principal Investigator: David Veesler
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2022
Award: $881,853
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY – PROJECT 1: Definition of the structural principles underlying broadly
protective humoral immunity
Although the COVID-19 pandemic has accelerated the development of SARS-CoV-2 vaccines at an
unprecedented pace, no licensed vaccines elicit broad protection against a large spectrum of human
coronaviruses. There is therefore an urgent need for vaccines inducing broad protection against currently
circulating and distantly related betacoronaviruses for pandemic preparedness. The proposed Project aims to
identify epitopes targeted by cross-reactive and broadly neutralizing anti-betacoronavirus antibodies to obtain
an antigenic map of targets present at the surface of betacoronavirus spike trimers to guide our vaccine design
efforts. Broadly neutralizing sarbecovirus antibodies recognizing the spike receptor-binding domain have
recently been discovered, however, they do not cross-react with members of other subgenera. Previous studies
have shown that the spike fusion machinery (S2 subunit), which is more conserved than the S1 subunit, harbors
conserved epitopes targeted by cross-reactive polyclonal antibodies. Although a few β-coronavirus cross-
reactive monoclonal antibodies are known, a deep understanding of the diversity of epitopes targeted by broadly
neutralizing antibodies and their quantitative contribution to neutralization is lacking, thereby hindering the
rational design of vaccines eliciting broad immunity. We will use three approaches to determine the molecular
determinants of broad antibody-mediated coronavirus immunity by unveiling the types, specificities, and diversity
of broadly neutralizing antibodies targeting all three main betacoronavirus subgenera (sarbecovirus,
merbecovirus, and embecovirus). First, we will characterize the binding and neutralizing breath of polyclonal
sera from nonhuman primates immunized with nanoparticle vaccines co-displaying multiple different RBD- and
spike-based antigens. Second, we will determine the epitope specificities of cross-reactive antibodies in these
sera using serological assays and by directly visualizing polyclonal antibodies in complex with vaccine-matched
and heterologous antigens using cryo-electron microscopy. Finally, we will isolate monoclonal antibodies from
nonhuman primates immunized with multivalent nanoparticle vaccines and characterize their structures at high
resolution as well as their binding, neutralizing, and protective breadth.
Terms: <2019-nCoV vaccine><Animals><Antibodies><Antibody Response><Antigenic Determinants><Antigens><Assay><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><Blood Plasma Cell><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 vaccine><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 vaccine><Clinical Treatment Moab><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><Complex><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Crab-Eating Macaque><Crab-Eating Monkey><Cryo-electron Microscopy><Cryoelectron Microscopy><Cynomolgus Monkey><Cynomolgus macaque><Development><Distant><ELISA><Electron Cryomicroscopy><Enzyme-Linked Immunosorbent Assay><Epitopes><Escape Mutant><Glycoproteins><H-D Antigens><HCoV><Hanganutziu-Deicher Antigens><Heteroantigens><Heterogenetic Antigens><Heterologous Antigens><Heterophil Antigens><Heterophile Antigens><Human><Humoral Immunities><Immunity><Immunize><M fascicularis><M. fascicularis><Macaca><Macaca fascicularis><Macaque><Maps><Mediating><Memory B Cell><Memory B-Lymphocyte><Merbecovirus><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Mosaicism><Murine><Mus><Paul-Bunnell Antigens><Plasma Cells><Plasmacytes><Resolution><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 vaccine><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-CoV2 vaccine><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><Sarbecovirus><Serology test><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccine><Specificity><Structure><Surface><Vaccinated><Vaccination><Vaccine Design><Vaccines><Virus><Work><Xenoantigens><Xenogeneic Antigens><Xenogenic Antigens><antibody-based immunity><base><beta CoV><beta coronavirus><betaCoV><betacoronavirus><corona virus><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><coronavirus S protein><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 vaccine><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><coronavirus spike glycoprotein><coronavirus vaccine><cross reactivity><cryo-EM><cryoEM><design><designing><developmental><enzyme linked immunoassay><human CoV><human corona virus><human coronavirus><immunogen><mAbs><member><mosaic disorders><mutation scanning><mutation screening><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><non-human primate><nonhuman primate><pandemic preparedness><plasmocyte><polyclonal antibody><protective efficacy><rational design><receptor binding><receptor bound><response><serology assay><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine against coronavirus><vaccine for novel coronavirus><β CoV><β coronavirus><βCoV>