Document text
Principal Investigator: Aaron Gregory Schmidt
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2022
Award: $1,934,136
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The global pandemic caused by Severe Acute Respiratory Syndrome virus 2 (SARS-CoV-2) coronavirus (CoV)
has highlighted the need to develop next-generation viral vaccines that offer protection against future
Sarbecoviruses and Merbecoviruses of concern. One approach is to implement structure-based immunogen
design strategies that elicit humoral responses to conserved sites on the surface-exposed spike (S) viral
glycoprotein. Potential sites include the receptor binding domain (RBD) and the receptor binding motif (RBM)
required for viral entry. Other conserved sites on S, outside the RBD, may also be targets of both neutralizing
and non-neutralizing responses offering broad CoV protection. Project 1 will combine computational, structural,
biophysical, and single B cell analyses to design S and RBD immunogens that elicit broad-spectrum humoral
immunity against CoVs. Based on evolutionary analysis of CoV sequences, it is unlikely that a single antigen will
confer broad enough immunity against the entire Betacoronavirus genus; we therefore anticipate generating a
polyvalent S or RBD containing vaccine (with Project 3). Initially, we prioritize ACE2-receptor using CoVs as a
proof-of-concept but envision that our design principles can be extended to other emerging CoVs where ACE2
is not the receptor. The Schmidt laboratory will implement structure-guided immunogen design strategies to
focus immune responses towards conserved epitopes on the RBM and RBD. We will use heterologous CoV
RBDs as molecular scaffolds to present selected ACE2-binding CoV RBMs and further immune focus using
engineered glycans to mask non-conserved epitopes. The Scheuermann laboratory will use ancestral
reconstructions to identify extant CoVs as additional S-based immunogens. The Ellebedy laboratory will isolate
monoclonal antibodies (mAbs) from naturally infected, vaccinated, or naïve human subjects to define CoV cross-
reactive, conserved epitopes on S recognized by neutralizing and non-neutralizing mAbs. We will define the
breadth of mAb cross-reactivity, cross-neutralization, and effector functions (with Project 3). The Fremont
laboratory will perform structural analyses by X-ray crystallography and cryo-electron microscopy (Fremont
laboratory) of the isolated mAbs to define targeted epitopes on S; this information will aid in iterative immunogen
optimization to elicit responses to these newly defined, cross-reactive epitopes. The output of Project 1 will be
optimized RBD and S genes to transfer to Project 3 for vaccine formulation in VSV or ChAd vaccine platforms.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Antibodies><Antigenic Determinants><Antigens><Assay><Avidity><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Bioassay><Biochemical><Biologic Assays><Biological Assay><Biophysics><COVID-19 virus><COVID19 virus><Cell Body><Cells><Chad><Clinical Treatment Moab><CoV emergence><CoV-2><CoV2><Complex><Coronaviridae><Coronavirus><Cryo-electron Microscopy><Cryoelectron Microscopy><Development><Electron Cryomicroscopy><Engineering><Epitopes><Evaluation><Frequencies><Future><Genes><Glycans><Glycoproteins><History><Humoral Immunities><Immune><Immune response><Immunes><Immunity><Immunological response><Laboratories><Link><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Masks><Merbecovirus><Metabolic Glycosylation><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><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monoclonal Antibodies><Output><Polysaccharides><Protein Binding Domain><Protein Binding Motif><Protein-Protein Interaction Domain><Proteins><Receptor Protein><Recombinants><Recording of previous events><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sarbecovirus><Serology><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Single Crystal Diffraction><Site><Structure><Surface><System><VSV><Vaccinated><Vaccinee><Vaccines><Variant><Variation><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Vaccines><Virus><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody-based immunity><base><beta CoV><beta coronavirus><betaCoV><betacoronavirus><biophysical foundation><biophysical principles><biophysical sciences><conformation><conformational state><corona virus><corona virus emergence><coronavirus disease 2019 virus><coronavirus disease-19 virus><coronavirus emergence><coronavirus receptor><cross reactivity><cross-link><crosslink><cryo-EM><cryoEM><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><glycosylation><hCoV19><host response><human subject><immune system response><immunogen><immunogenicity><immunoresponse><interest><lumazine><mAbs><nCoV><nCoV2><nano particle><nano-sized particle><nanoparticle><nanosized particle><new CoV><new corona virus><new coronavirus><next generation><non-Native><nonnative><novel CoV><novel corona virus><novel coronavirus><pan CoV vaccine><pan coronavirus vaccine><panCoV vaccine><pancoronavirus vaccine><pandemic><pandemic disease><rational design><receptor><receptor binding><receptor bound><reconstruction><response><scaffold><scaffolding><severe acute respiratory syndrome-CoV><social role><universal CoV vaccine><universal coronavirus vaccine><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine development><vaccine formulation><vaccine platform><vector><β CoV><β coronavirus><βCoV>