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Principal Investigator: Mark Morris Davis
Organization: STANFORD UNIVERSITY
Fiscal Year: 2022
Award: $309,746
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT – Project 2
The goal of Project 2 is to assess T cell responses in the context of proposed studies of: (i) COVID-19
vaccines that utilize novel platforms (mRNA) or adjuvants (Matrix M used in the Novavax vaccine) and (ii)
Humans given broad spectrum antibiotics that disrupt their microbiome, prior to and during rabies vaccination.
This goal is highly synergistic with those of Projects 1 and 3, which will evaluate innate and B cell responses
respectively, in the context of the same clinical trials. We will use new developed state-of-the-art techniques
that will allow us to probe the vaccine responses here with an unprecedented scale and depth. The three
methods are: (1) spheromer probes for specific T cells, (2) GLIPH (for Grouping of Lymphocyte Interactions by
Paratope Hotspots) analysis of TCR specificity groups, and (3) immune organoids. We will apply these tools in
the following aims:
Aim 1: Assessment of T cell responses to vaccination against COVID-19.
Sub-aim 1a. Analyze T cell responses induced by the BNT162b2 mRNA vaccine in healthy versus atopic
individuals. We will use the spheromer technology mentioned above, to create and use a panel of pMHC
Spheromers SARS-CoV-2 spike epitopes covering the major class I and II HLA alleles, to analyze the T cell
response, in healthy versus atopic subjects. In addition, we will perform TCR repertoire analysis using GLIPH2
to analyze both bulk and single cell TCR sequences in order to define the frequency, phenotype, function and
TCR diversity of antigen specific T cell responses to primary and secondary vaccination in blood and the
draining lymph nodes of both healthy adults and allergy prone subjects.
Sub-aim 1b: Assessment of T cell responses induced by the Novavax Matrix-M adjuvanted subunit vaccine.
We will also analyze samples collected from a Novavax sponsored trial done at the University of Witwatersrand
with spheromers and TCR sequence analysis and determine how the response to an adjuvanted subunit
vaccine differs from that induced by mRNA vaccination
Aim 2: Assessment of the impact of the microbiota on the antigen-specific T cell response to
vaccination. We will assess the impact of broad-spectrum antibiotics on the primary T cell response to rabies
vaccination. In particular, we will analyze the TCR repertoire and phenotype of T cells responding to this
vaccine, since there are clear indications that the microbiome can influence T cell phenotype, and we
hypothesize that there might be an influence on the repertoire as well.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><21+ years old><Adjuvant><Adult><Adult Human><Algorithms><Alleles><Allelomorphs><Allergic Reaction><Allergy><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibody Binding Sites><Antigenic Determinants><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><BNT 162b2><BNT162b2><Binding Determinants><Blood><Blood Reticuloendothelial System><CDR3-region><COVID-19><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID19><COVID19 vaccination><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical Trials><CoV-2><CoV2><Complementarity Determining Region 3><Complementarity Determining Region III><Defect><Epitopes><Exposure to><Ferritin><Frequencies><GI microbiota><Gastrointestinal microbiota><Goals><Grouping><Human><Hypersensitivity><Immune><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Individual><Innate Immunity><Label><Lymphatic cell><Lymphocyte><Lymphocytic><Messenger RNA><Methods><Miscellaneous Antibiotic><Modern Man><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Organoids><Paratopes><Peptide-MHC><Peptide-Major Histocompatibility Protein Complex><Peptide/MHC Complex><Peptides><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Phenotype><Probability><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Rabies><Reporting><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SEQ-AN><Sampling><Sequence Analyses><Sequence Analysis><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 CoV 2 vaccine><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 coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Specificity><Spinal Column><Spine><Staining method><Stains><Subcellular Process><Subunit Vaccines><Survey Instrument><Surveys><T cell response><T-Cells><T-Lymphocyte><T-cell receptor repertoire><TCR repertoire><Techniques><Technology><Universities><Vaccination><Vaccines><Vertebral column><Wuhan coronavirus><adaptive immunity><adult youth><adulthood><antibody combining site><antigen-specific T cells><backbone><base><biological systems><cohort><combinatorial><comparator group><comparison group><complementarity-determining region 3><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><draining lymph node><enteric microbial community><enteric microbiota><falls><gastrointestinal microbial flora><groupings><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><hCoV19><intestinal flora><intestinal microbes><intestinal microbiota><intestinal microflora><intestinal tract microflora><lymph cell><lyssa><mRNA><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><microbial consortia><microbial flora><microbiome><microbiota><microflora><multispecies consortia><nCoV2><novel><outcome following vaccination><outcome following vaccine><pMHC><phenotypic biomarker><phenotypic marker><regional lymph node><response><result following vaccination><result following vaccine><seasonal flu><seasonal influenza><third complementarity-determining region><thymus derived lymphocyte><tool><vaccinate against COVID-19><vaccinate against COVID19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against COVID19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccination outcome><vaccination result><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 for novel coronavirus><vaccine outcome><vaccine response><vaccine responsiveness><vaccine result><vaccine-induced response><young adult><young adulthood>