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Principal Investigator: YOSHIHIRO KAWAOKA
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2023
Award: $2,819,456
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
As part of the Pan-Coronavirus Vaccine (PanCoVac) Consortium, the goal of Research Project 1 (RP1) is
the ‘Design and evaluation of pan-CoV vaccines’. A comprehensive characterization of the B and T cell
responses to vaccination will be carried out by Research Project 2 (RP2, ‘Immunological responses to pan-CoV
vaccines. In Aim 1 of RP1 (‘Focusing immune responses towards the stem of the spike protein’), several
strategies will be tested to increase the levels of antibodies directed at the conserved, immune-subdominant
epitopes in the stem of the SARS-CoV-2 spike protein (to major viral antigen), while avoiding strong antibody
responses directed at immunodominant epitopes in the head of the spike protein. These strategies include
chimeric spikes composed of SARS-CoV-2 immune-subdominant stem epitopes and immunodominant head
epitopes of unencountered coronaviruses, ‘outdiluting’ antibody responses to the immunodominant epitopes by
using cocktails of spike proteins with multiple mutations in key amino acid positions, glycan-shielding of
immunodominant head epitopes, ‘inverted antigens’ in which the spike protein will be presented to the immune
system in an inverted orientation (and thus become more accessible), and ‘headless’ spike proteins lacking
portions of the immunodominant head epitopes. Some of these approaches may be tested in combination, and
may be tested with sequence-optimized stem epitopes based on ancestral reconstruction (a computational
approach to deduce the most likely common progenitor sequence). In Aim 2 (‘Eliciting broadly reactive
immune responses to the head of the spike protein’), strategies will be tested to direct the immune responses
away from the most sequence-diverse epitopes and towards more conserved epitopes in the head. In addition,
conserved heard epitopes will be sequenced-optimized to be recognized by cross-protective antibodies. These
modifications will be introduced into diverse spike proteins, and vaccine cocktails of diverse, mutant spike
proteins will then be tested for their immunogenicity and protective efficacy. All antigens in Aims 1 and 2 will be
designed in collaboration with a structural biologist, and for selected antigens and/or antigen/antibody complexes,
X-ray crystallography and Cryo-EM will be carried out. In Aim 3 (‘Immunogenicity and protective efficacy of
broadly reactive antigens’), the novel vaccinates will be tested in mice for their immunogenicity; samples from
vaccinated mice will be provided to RP2 for B and T cell analysis. Selected vaccine candidates (those with
broader immune responses) will next be tested in mice and Syrian hamsters for their ability to provide protection
against different coronaviruses. For candidate vaccines that provide broad protection (compared to controls), we
will also assess the durability of immune responses, and the effect of vaccination on virus transmissibility.
Moreover, these vaccinate candidates will be tested in an mRNA lipid nanoparticle vaccine platform provided by
Daiichi Sankyo, a pharmaceutical company.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Amino Acids><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antibody titer measurement><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bacteriophage MS2><Binding Determinants><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><Chicago><Chimera><Chimera organism><CoV S protein><CoV emergence><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Coliphage MS2><Collaborations><Complex><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Development><Early-Stage Clinical Trials><Electron Cryomicroscopy><Encapsulated><Enterobacteria phage MS2><Epitopes><Evaluation><Funding Opportunities><Genetic Alteration><Genetic Change><Genetic defect><Glycans><Goals><Golden Hamsters><Golden Syrian Hamsters><Head><Hearing><Human><Immune><Immune response><Immune system><Immunes><Immunization><Immunize><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Immunological response><Immunology><Individual><Influenza HA><Influenza Hemagglutinin><Influenza Vaccines><Influenza Virus><Japan><Laboratories><MS2 Phage><Mesocricetus auratus><Messenger RNA><Mice><Mice Mammals><Modern Man><Modification><Molecular Virology><Murine><Mus><Mutation><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase 1 Clinical Trials><Phase I Clinical Trials><Polysaccharides><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><Research Grants><Research Project Grants><Research Projects><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Saint Jude><Saint Jude Children's Cancer Center><Saint Jude Children's Research Hospital><Sampling><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-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Single Crystal Diffraction><St. Jude><St. Jude Children's Cancer Center><St. Jude Children's Research Hospital><St. Jude Children's Research Hospital Comprehensive Cancer Center><St.Jude Children's Cancer Center><St.Jude Children's Research Hospital><St.Jude Children's Research Hospital Comprehensive Cancer Center><Structural Biologist><Syrian Hamsters><System><T cell response><T-Cells><T-Lymphocyte><Testing><Universities><VSV><Vaccinated><Vaccination><Vaccines><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral Antigens><Virus><Virus-like particle><Wisconsin><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><aminoacid><antibody titering><bionano technology><bionanotechnology><candidate selection><chimeras><compare to control><comparison control><corona virus><corona virus emergence><coronavirus S protein><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19 virus><coronavirus emergence><coronavirus spike glycoprotein><coronavirus vaccine><cross reactivity><cryo-EM><cryoEM><cryogenic electron microscopy><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><flexibility><flexible><flu HA><flu hemagglutinin><flu vaccine><flu virus vaccine><genome mutation><hCoV19><host response><immune system response><immunogen><immunogenicity><immunoresponse><influenza viral HA><influenza viral hemagglutinin><influenza virus HA><influenza virus hemagglutinin><influenza virus vaccine><influenzavirus><lipid based nanoparticle><lipid nanoparticle><mRNA><model of animal><mutant><nCoV><nCoV2><nano biotechnology><nanobiotechnology><new CoV><new corona virus><new coronavirus><novel><novel CoV><novel corona virus><novel coronavirus><pan CoV vaccine><pan coronavirus vaccine><panCoV vaccine><pancoronavirus vaccine><pharmaceutical><phase I protocol><progenitor><protective efficacy><reconstruction><self assembly><stem><thymus derived lymphocyte><universal CoV vaccine><universal coronavirus vaccine><vaccine against coronavirus><vaccine against flu><vaccine against influenza><vaccine candidate><vaccine development><vaccine platform><virology><virus antigen><virus-like nanoparticles><viruslike particle>