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Principal Investigator: Michael S Diamond
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2022
Award: $2,161,141
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Over the past twenty years, six coronaviruses (CoV) have emerged or expanded their geographic range. The
emergent human CoVs with the greatest global impact (SARS-CoV-1, SARS-CoV-2, and MERS-CoV) belong to
the Sarbecovirus and Merbecovirus subgenera within the Betacoronavirus genus of the Coronaviridae family.
Many zoonotic high-risk Sarbecoviruses and Merbecoviruses are poised for human emergence events because
they can bind human ACE2 and DPP4 entry receptors and infect human cells in culture. Given the historical
outbreaks of CoVs, coupled with the recent emergence of SARS-CoV-2 and its destabilizing consequence on
global health and economy, there is an urgent need to develop vaccines capable of broad protection against
existing and future Sarbecoviruses and Merbecoviruses. Thus, the overarching goal of this P01 proposal is to
generate viral-vectored vaccines that induce broad cross-protective humoral and cellular immunity to
Sarbecoviruses and Merbecoviruses with pandemic potential, especially those viruses at high risk for zoonotic
emergence into human populations. Project 3 will use antigen and epitope designs from Projects 1 and 2 to
create vaccine platforms that generate cross-reactive immune responses against Sarbecoviruses and
Merbecoviruses with pandemic potential. We will use several spike (S), RBD, and non-structural protein antigens
that can be administered as part of a polyvalent formulation to induce broad B and T cell immunity. Project 3
will perform parallel and iterative engineering of an intranasally delivered chimpanzee adenoviral vectored virus
(ChAd) and an intramuscularly delivered live-attenuated vesicular-stomatitis virus (VSV) displaying or producing
optimized antigens. Antigens and vaccines that show immune responses of the highest magnitude and greatest
cross-reactivity (determined with Core A) will be tested in in naïve, virus-immune, and mRNA vaccinated mice
to determine how pre-existing immunity to SARS-CoV-2 impacts the immunogenicity of our more broadly
targeting CoV vaccines. Vaccines showing optimal B and T cell immunogenicity (breadth, magnitude, and
function) will be prioritized for mouse and hamster challenge studies in Core B with multiple Sarbecoviruses and
Merbecoviruses. Our proposal is a proof-of-principle for product development. We envision generating at least
one vaccine that induces broad-spectrum immunity to multiple CoV of concern.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Ad vector><Adenoviral Vector><Adenovirus Vector><Animals><Antibodies><Antibody Response><Antigenic Determinants><Antigens><Attenuated><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><BNT 162b2><BNT162b2><Binding><Binding Determinants><Blocking Antibodies><C-terminal><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 virus><COVID19 virus><Cell Body><Cell Mediated Immunology><Cell membrane><Cell surface><Cell-Mediated Immunity><Cells><Cellular Immunity><Chad><Chimp><Chimpanzee><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Coupled><Cricetinae><Cytoplasmic Membrane><Development><Diamond><Disease Outbreaks><Dose><Engineering><Epitopes><Evaluation><Event><Family><Formulation><Future><G-Proteins><GTP-Binding Proteins><GTP-Regulatory Proteins><Genes><Geography><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><HCoV><Hamsters><Hamsters Mammals><Human><Humoral Immunities><Immune><Immune response><Immunes><Immunity><Immunological response><Individual><Infection><Intramuscular><Intramuscular Injections><Laboratories><Length><Link><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Merbecovirus><Messenger RNA><Mice><Mice Mammals><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 Interaction><Mucosal Immunity><Murine><Mus><Non-structural Protein><Nonstructural Protein><Outbreaks><Pan Genus><Pan Species><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Plasma Membrane><Population><Proteins><RNA vaccine><RNA-based vaccine><Receptor Protein><Regimen><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><System><T cell response><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TM Domain><Testing><Transgenic Mice><Transmembrane Domain><Transmembrane Region><VSV><Vaccinated><Vaccines><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral Vaccines><Viral Vector><Virus><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><adeno vector><adenovector><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody-based immunity><base><beta CoV><beta coronavirus><betaCoV><betacoronavirus><cell transduction><cellular transduction><corona virus><coronavirus S protein><coronavirus disease 2019 virus><coronavirus disease-19 virus><coronavirus spike glycoprotein><coronavirus vaccine><cross reactivity><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><experience><global health><hCoV19><high risk><host response><human CoV><human corona virus><human coronavirus><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><intramuscular drug administration><mRNA><mRNA vaccine><mRNA-based vaccine><member><nCoV2><pan CoV vaccine><pan coronavirus vaccine><panCoV vaccine><pancoronavirus vaccine><pandemic><pandemic disease><plasmalemma><plasmid vaccine><product development><receptor><receptor binding><receptor bound><response><seasonal coronavirus><severe acute respiratory syndrome-CoV><thymus derived lymphocyte><transduced cells><universal CoV vaccine><universal coronavirus vaccine><vaccine against coronavirus><vaccine development><vaccine efficacy><vaccine platform><vector><vector vaccine><β CoV><β coronavirus><βCoV>