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Principal Investigator: David A. Hafler
Organization: YALE UNIVERSITY
Fiscal Year: 2023
Award: $483,750
Funding agency: National Institute of Allergy and Infectious Diseases
Elucidating mechanisms of novel mRNA nanoparticle and adenovirus-viral vector vaccine-
induced T and B cell activation at the site of vaccination and lymph nodes is of critical
importance. Studying patients with autoimmune disease treated with B cell depletion, we will
perform a systems analysis to examine dynamics of immune response to SARS-CoV-2
vaccination in the context of B cell depletion. As part of our previous HIPC project, we studied T-
B cell interactions in the acute phase of COVID-19 disease and found that PD-1high CXCR5–
CD4+ peripheral helper T (Tph) cells were increased and exhibited B cell help signatures.
Activated HLA-DR+CD38+ Tph cells were highly correlated with titers of anti-S1/RBD antibodies
and improved clinical outcome. As Tph cells are known for supporting the generation of
pathogenic autoantibodies and COVID-19 patients display autoantibody signatures, Tph cells
may play dual roles in COVID-19 infection driving recovery and long-term adverse autoimmune
sequel. Thus, we hypothesize that in response to vaccination, B cells affect the induction of
antigen specific T cells and Tph cells required for antibody production. In Aim 1a , we will
elucidate immune response signatures to SARS mRNA vaccination with B cell depletion. In
depth functional profiling of immune cells will be accomplished with CyTOF, 10x scRNA
sequencing with BCR/TCR analysis and CITE-seq and proteomics. Analysis of autoantibody
production will be conducted with the REAP platform to determine whether SARS-CoV-2
vaccinations induce autoantibodies and whether they are attenuated with B cell depletion. In
Aim 1b, early events in the immune response to vaccination in B cell depleted patients and
controls will be analyzed near the inoculation site and in draining lymph nodes determining
whether Tph cells involved in ectopic antibody production are induced at the site of vaccination.
In Aim 1c, we will measure antigen specific responses to viral peptides using oligo-conjugated
MHC tetramers with CITE-seq technology. We will elucidate immune signatures to a booster
vaccination in B cell depleted patients in Aim 2a, and compare the response between MF59-
adjuvanted flu vaccine and standard-dose flu vaccine in Aim 2b. We will determine whether
responses to SARS-CoV-2 and flu vaccines correlate and if the MF59 adjuvant enhances
immune response with B cell depletion. In total, this systems approach will allow us to elucidate
the role of B cells in inducing immune responses with novel mRNA vaccines.
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