Systems biological assessment of T cell responses to vaccination

T 细胞对疫苗接种反应的系统生物学评估

• 批准号: 10584571
• 负责人: Mark Morris Davis
• 金额: $ 37.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-07 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584571
• 关键词: 2019-nCoV; Adjuvant; Adult; Algorithms; Alleles; Allergic Reaction; Antibiotics; Antibody Binding Sites; B-Lymphocytes; Blood; COVID-19; COVID-19 vaccination; COVID-19 vaccine; Cells; Clinical Trials; Defect; Epitopes; Exposure to; Ferritin; Frequencies; Goals; Grouping; Human; Hypersensitivity; Immune; Immunologics; Individual; Label; Lymphocyte; Messenger RNA; Methods; Natural Immunity; Organoids; Peptide/MHC Complex; Peptides; Pfizer-BioNTech COVID-19 vaccine; Phenotype; Probability; RNA vaccination; RNA vaccine; Rabies; Reporting; Sampling; Sequence Analysis; Specificity; Stains; Subunit Vaccines; Surveys; T cell response; T-Lymphocyte; T-cell receptor repertoire; Techniques; Technology; Universities; Vaccination; Vaccines; Vertebral column; adaptive immunity; antigen-specific T cells; biological systems; cohort; combinatorial; complementarity-determining region 3; draining lymph node; falls; gut microbiota; influenza virus vaccine; microbiome; microbiota; novel; phenotypic biomarker; response; seasonal influenza; success; tool; vaccine response; young adult

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.

摘要 – 项目 2 项目 2 的目标是在拟议研究的背景下评估 T 细胞反应：(i) COVID-19 利用新平台 (mRNA) 或佐剂（Novavax 疫苗中使用的 Matrix M）的疫苗和 (ii) 在狂犬病疫苗接种之前和期间，人类服用了破坏微生物群的广谱抗生素。 该目标与项目 1 和 3 的目标高度协同，项目 1 和 3 将评估先天细胞和 B 细胞反应 分别在相同的临床试验中进行。我们将使用新开发的最先进的技术 这将使我们能够以前所未有的规模和深度探索这里的疫苗反应。三个 方法有：(1) 针对特定 T 细胞的球体探针，(2) GLIPH（用于对淋巴细胞相互作用进行分组） 互补位热点）TCR 特异性组的分析，以及（3）免疫类器官。我们将应用这些工具 目标如下： 目标 1：评估 T 细胞对 COVID-19 疫苗接种的反应。 分目标 1a。分析 BNT162b2 mRNA 疫苗在健康人群与特应性人群中诱导的 T 细胞反应 个人。我们将使用上面提到的 spheromer 技术，创建并使用 pMHC 面板 Spheromers SARS-CoV-2 刺突表位覆盖主要的 I 类和 II 类 HLA 等位基因，用于分析 T 细胞 健康受试者与特应性受试者的反应。此外，我们将使用 GLIPH2 进行 TCR 谱分析 分析批量和单细胞 TCR 序列，以确定频率、表型、功能和 血液中抗原特异性 T 细胞对初次和二次疫苗接种反应的 TCR 多样性以及 健康成人和易过敏受试者的淋巴结引流。 子目标 1b：评估 Novavax Matrix-M 佐剂亚单位疫苗诱导的 T 细胞反应。 我们还将分析从 Novavax 赞助的威特沃特斯兰德大学进行的试验中收集的样本 通过球体和 TCR 序列分析，确定对佐剂亚基的反应 疫苗与 mRNA 疫苗接种诱导的疫苗不同 目标 2：评估微生物群对抗原特异性 T 细胞反应的影响 疫苗接种。我们将评估广谱抗生素对狂犬病初级 T 细胞反应的影响 疫苗接种。特别是，我们将分析对此作出反应的 T 细胞的 TCR 库和表型 疫苗，因为有明确的迹象表明微生物组可以影响 T 细胞表型，而且我们 假设这也可能对曲目产生影响。