Systems investigation of vaccine responses in B cell depleted autoimmune patients

点击翻译按钮获取中文摘要

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.