Systems investigation of vaccine responses in B cell depleted autoimmune patients

B 细胞耗尽的自身免疫患者疫苗反应的系统研究

• 批准号: 10617759
• 负责人: David A. Hafler
• 金额: $ 48.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617759
• 关键词: 2019-nCoV; Acute; Adenoviruses; Adjuvant; Affect; Age; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Antigen-Presenting Cells; Antigens; Attenuated; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; B cell therapy; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; BLR1 gene; Blood; COVID-19; COVID-19 booster; COVID-19 mortality; COVID-19 patient; COVID-19 vaccination; Cell Communication; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Custom; Dendritic cell activation; Disease; Dose; Elements; Event; Exhibits; Frequencies; Generations; HLA-DR Antigens; Hemagglutinin; Immune; Immune response; Immunity; Immunization; Impairment; Individual; Influenza; Investigation; MF59; Measures; Messenger RNA; Methodology; Oligonucleotides; Outcome; Pathogenicity; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Plasmablast; Play; Production; Proteins; Proteomics; Protocols documentation; RNA vaccination; RNA vaccine; Recovery; Role; SARS-CoV-2 infection; SARS-CoV-2 spike protein; SARS-CoV-2 variant; Secondary Immunization; Severe Acute Respiratory Syndrome; Site; Skin; System; Systems Analysis; T cell response; T-Lymphocyte; Technology; Time; Vaccination; Vaccines; Viral; Viral Vaccines; Viral Vector; Virus Diseases; Vulnerable Populations; antigen challenge; antigen-specific T cells; cohort; draining lymph node; extracellular; flu; genetic signature; improved; influenza virus vaccine; investigator-initiated trial; lipid nanoparticle; lymph nodes; nanoparticle; novel; pathogenic autoantibodies; programmed cell death protein 1; response; sensor; sex; single-cell RNA sequencing; transcriptomics; vaccine response; vaccine strategy; vector vaccine

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.

阐明新型 mRNA 纳米颗粒和腺病毒-病毒载体疫苗的机制- 在疫苗接种部位和淋巴结诱导 T 细胞和 B 细胞活化至关重要 重要性。研究接受 B 细胞去除治疗的自身免疫性疾病患者，我们将 进行系统分析以检查对 SARS-CoV-2 免疫反应的动态 B 细胞耗竭背景下的疫苗接种。作为我们之前的重债穷国项目的一部分，我们研究了 T- COVID-19 疾病急性期的 B 细胞相互作用，发现 PD-1high CXCR5– CD4+ 外周辅助 T (Tph) 细胞增加并表现出 B 细胞辅助特征。 激活的 HLA-DR+CD38+ Tph 细胞与抗 S1/RBD 抗体滴度高度相关 并改善临床结果。由于 Tph 细胞以支持产生 致病性自身抗体和 COVID-19 患者表现出自身抗体特征、Tph 细胞 可能在 COVID-19 感染推动康复和长期不良自身免疫方面发挥双重作用 续集。因此，我们假设，作为对疫苗接种的反应，B 细胞会影响 抗体产生所需的抗原特异性 T 细胞和 Tph 细胞。在目标 1a 中，我们将 阐明 B 细胞耗竭对 SARS mRNA 疫苗接种的免疫反应特征。在 将使用 CyTOF、10x scRNA 完成免疫细胞的深度功能分析 通过 BCR/TCR 分析、CITE-seq 和蛋白质组学进行测序。自身抗体分析 将使用 REAP 平台进行生产，以确定是否 SARS-CoV-2 疫苗接种会诱导自身抗体产生，以及它们是否会因 B 细胞耗竭而减弱。在 目标 1b，B 细胞耗尽患者对疫苗接种的免疫反应的早期事件和 对照将在接种部位附近和引流淋巴结中进行分析以确定 参与异位抗体产生的 Tph 细胞是否在疫苗接种部位被诱导。 在目标 1c 中，我们将使用寡核苷酸缀合来测量对病毒肽的抗原特异性反应 采用 CITE-seq 技术的 MHC 四聚体。我们将阐明加强剂的免疫特征 在目标 2a 中对 B 细胞耗尽的患者进行疫苗接种，并比较 MF59- 之间的反应 目标 2b 中的佐剂流感疫苗和标准剂量流感疫苗。我们将确定是否 对 SARS-CoV-2 和流感疫苗的反应相关，并且 MF59 佐剂是否增强 B 细胞耗竭的免疫反应。总的来说，这种系统方法将使我们能够阐明 B 细胞在新型 mRNA 疫苗诱导免疫反应中的作用。