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Principal Investigator: PAUL JOSEPH UTZ
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $762,036
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
The overarching goal of the proposed study is to better understand COVID-19 vaccine immunogenicity in
immunocompromised individuals, particularly patients with connective tissue diseases (CTDs) and other
musculoskeletal disorders. A paucity of data exists regarding vaccine safety, immunogenicity, efficacy, durability
and especially mechanisms of vaccine responses in AID patients, leading to an unmet need to elucidate these
critical mechanisms. We performed a “systems vaccinology” study of the BNT162b2 (Pfizer-BioNTech) mRNA
vaccine in 18 patients with systemic lupus erythematosus (SLE), using multiple methods including single cell
profiling technologies. We showed vaccination was generally safe but led to minor disease flares in a subset of
patients. Vaccine efficacy, based on anti-spike IgG responses and pseudovirus neutralization assays for multiple
SARS-CoV-2 variants of concern (VoC), were highly variable and not fully explained by immunosuppressive
medications. Vaccine nonresponders (NR) had severely blunted induction of IFN-γ, CXCL9, CXCL10, and
CXCL11 proteins following vaccine boost. SLE patients had universally lower frequency of CD8+ and CD4+
spike-specific T cells throughout the vaccination series. This R01 application proposes 3 aims. Aim 1 will enroll
an expanded SLE longitudinal COVID-19 vaccine cohort and a new SSc vaccine cohort. We will continue to
follow the SLE inception cohort to determine how their immune responses evolve with future COVID vaccines.
In parallel, we will enroll two new cohorts, one in SLE and the second in SSc, a disease which shares several
features including AAb, anti-cytokine AAbs (ACA), and lung and skin pathology. We will test the hypothesis that
immune mechanisms of vaccine responses will be shared between diseases, but that differences in autoreactive
B and T cell receptors, antibody repertoires, and innate immunity will be discovered. We will compare CTDs with
each other and with healthy people, across vaccine platforms (e.g., mRNA vaccines, protein vaccines, and DNA
vaccines) currently in development for COVID-19 prevention. Aim 2 will characterize adaptive immune responses.
We will characterize antibodies, T cells, and B cells. Antibodies will be measured using custom, bead-based
arrays for measurement of AAbs and ACA to ensure vaccines do not enhance secretion of existing or new AAb
after vaccination; and anti-viral IgG responses, including in vitro and pseudoviral functional blocking assays
against emerging VoC over time. B cell studies will include B cell receptor (BCR) repertoires and transcription
modules, and creation and analysis of recombinant monoclonal Ab (rMAb); T cell studies will include phenotyping
of virus-specific T cells using MHC Class I and II spheromers. T cell populations known to be associated with
AID, will be studied. Aim 3 will characterize COVID-19 vaccine responses in the innate immune compartment.
The role of innate immune cells will be explored using bulk-RNA-seq, measurement of plasma analytes using
“omics” technologies, and Epigenetic profiling by Time of Flight (EpiToF) to measure “innate memory”. CITE-seq
will then be used to deeply phenotype innate immune cells from responders and NR.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV vaccine><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Antibodies><Antibody Repertoire><Antigens><Assay><Autoantibodies><Autoimmune Diseases><B blood cells><B cell><B cell receptor><B cell repertoire><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><BNT 162b2><BNT162b2><Bioassay><Biological Assay><Blood><Blood Plasma><Blood Reticuloendothelial System><CD8><CD8B><CD8B1><CD8B1 gene><CITE sequencing><CITE-seq><CITEseq><COVID-19><COVID-19 S protein><COVID-19 infection><COVID-19 prevention><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccination><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus infection><COVID19 infection><CRG-2><CV-19><CXC 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