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Principal Investigator: BALI PULENDRAN
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2022
Award: $1,377,304
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY– PROJECT 3: Mechanistic studies and comparisons of vaccines in preclinical
models
The two primary goals of the Project are to: (i) define the immunological parameters (i.e., CD4+ T cell help;
innate immune response) that regulate the breadth of the antibody response in mechanistic studies in mice,
and (ii) evaluate pan-sarbecovirus and pan-betacoronavirus vaccine candidates aimed at inducing broadly
protective immune responses in nonhuman primates (NHPs) (with Core D, Nonhuman Primates, Villinger).
In Aim 1, we will determine the mechanisms by which the innate immune system and T follicular cells regulate
the breadth of antibody responses induced by broadly protective coronavirus vaccines designed in Project 2
(King). We will perform mechanistic studies in mice to determine the impact of CD4+ T cell help and specific
DC subsets in regulating the breadth of vaccine-elicited Ab responses. This will yield insights about critical
immunological parameters that determine antibody breadth and, looking ahead, provide a rational basis for the
development of adjuvants that stimulate broad Ab responses. In Aim 2 we will conduct two studies in NHPs to
evaluate pan-sarbecovirus and pan-betacoronavirus vaccine candidates from Project 2 and select lead
candidates for further preclinical and clinical development. These studies will use clinically relevant adjuvants
to ensure optimal translation to humans. We will assess the magnitude, breadth and durability of nAb
responses induced by immunization with nanoparticle immunogens formulated with AS03 and 3M-052/alum,
both of which have demonstrated superior adjuvant effects in terms of their capacity to promote
high-magnitude and durable neutralizing antibody responses in NHPs. We will thus directly compare AS03 with
3M-052/alum for their capacity to enhance the breadth of nAb responses. We will work with Project 1
(Veesler) and Cores B (Virology, Baric), C (Viral Evolution, Bloom) and D to evaluate the immunogenicity
and protective breadth of the responses elicited by each nanoparticle vaccine candidate and define the epitope
specificities of cross-reactive responses. We will characterize the dynamics of the antigen-specific B cell
response, assess plasmablast and plasma cell frequencies, and sort antigen-specific single B cells and isolate
monoclonal antibodies from immunized NHPs. These mAbs will be produced by Core A (Protein Sciences,
King) and analyzed in Project 1 and Cores B and C for their binding and neutralizing breadth, epitope
specificity, and resistance to escape mutations.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><Ab response><Adjuvant><Alum Adjuvant><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Blood><Blood Plasma Cell><Blood Reticuloendothelial System><Bone Marrow><Bone Marrow Reticuloendothelial System><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><Cell Body><Cells><Clinical Treatment Moab><Collaborations><Data><Dendritic Cells><Development><Early-Stage Clinical Trials><Emulsions><Ensure><Epitopes><Evaluation><Evolution><Frequencies><Genetic Alteration><Genetic Change><Genetic defect><Goals><H-D Antigens><Hanganutziu-Deicher Antigens><Heteroantigens><Heterogenetic Antigens><Heterologous Antigens><Heterophil Antigens><Heterophile Antigens><Human><Hydrogen Oxide><Immune response><Immunization><Immunize><Immunochemical Immunologic><Immunologic><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunostimulation><Innate Immune Response><Innate Immune System><Lead><Ligands><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Mice><Mice Mammals><Modern Man><Molecular Interaction><Monoclonal Antibodies><Mosaicism><Murine><Mus><Mutation><Oils><Patients><Paul-Bunnell Antigens><Pb element><Performance><Phase 1 Clinical Trials><Phase I Clinical Trials><Phylogeny><Plasma Cells><Plasmablast><Plasmacytes><Play><Pre-Clinical Model><Preclinical Models><Proteins><Resistance><Role><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><Sarbecovirus><Science><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Solid><Specificity><Squalene><Structure><Surface><Systems Biology><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TLR protein><TLR7><TLR7 gene><Toll-Like Receptor 7><Toll-Like Receptor Family Gene><Toll-like receptors><Vaccination><Vaccine Design><Vaccines><Veiled Cells><Viral><Viral Vaccines><Water><Work><Xenoantigens><Xenogeneic Antigens><Xenogenic Antigens><alum><aluminum sulfate><antibody biosynthesis><base><beta CoV><beta coronavirus><beta coronavirus vaccine><betaCoV><betacoronavirus><betacoronavirus vaccine><candidate selection><clinical development><clinical relevance><clinically relevant><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus vaccine><cross reactivity><cytokine><design><designing><developmental><genome mutation><heavy metal Pb><heavy metal lead><host response><immune system response><immunogen><immunogenic><immunogenicity><immunoglobulin biosynthesis><immunoresponse><insight><lead candidate><lymph gland><lymph nodes><lymphnodes><mAbs><model of animal><model organism><mosaic disorders><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><non-human primate><nonhuman primate><novel><panbetaCoV vaccine><phase I protocol><plasmocyte><pre-clinical development><preclinical development><programs><resistant><response><scaffold><scaffolding><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><social role><thymus derived lymphocyte><translation to humans><vaccine against coronavirus><vaccine candidate><variants of concern><virology><β CoV><β coronavirus><β coronavirus vaccine><βCoV>