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: 10419280
• 负责人: Mark Morris Davis
• 金额: $ 30.97万
• 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/10419280
• 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; Cell physiology; 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; base; biological systems; cohort; combinatorial; comparison group; complementarity-determining region 3; draining lymph node; falls; gut microbiota; microbiome; microbiota; novel; phenotypic biomarker; response; seasonal influenza; tool; vaccination outcome; 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的目的是在提出的研究的背景下评估T细胞反应：（i）COVID-19 利用新型平台（mRNA）或调节器（Novavax疫苗中使用的基质M）和（ii）的疫苗 人类在狂犬病疫苗接种之前和期间给予破坏其微生物组的广谱抗生素。 该目标与项目1和3的目标高度协同，这将评估先天和B细胞的响应 在同一临床试验的背景下分别。我们将使用新的发达最新技术 这将使我们能够在这里以前所未有的量表和深度探测疫苗反应。三个 方法是：（1）特定T细胞的球形问题问题，（2）GLIPH（用于分组淋巴细胞相互作用 寄生虫热点）TCR特异性组的分析，以及（3）免疫器官。我们将应用这些工具 以下目的： 目标1：评估T细胞对COVID-19的疫苗接种反应。 Sub-aim 1A。分析由健康与特应性的BNT162B2 mRNA疫苗诱导的T细胞反应 个人。我们将使用上面提到的球形组技术来创建和使用PMHC面板 Spheromers SARS-COV-2尖峰表位涵盖了主要I和II类HLA等位基因，以分析T细胞 反应，健康与特应学受试者。此外，我们将使用GLIPH2进行TCR曲目分析 分析批量和单细胞TCR序列，以定义频率，表型，功能和 TCR抗原特异性T细胞对血液中原发性和继发疫苗接种的反应的多样性， 健康成年人和易于过敏受试者的排水淋巴结。 子-IAM 1B：评估由Novavax Matrix-M调整后亚基疫苗诱导的T细胞反应。 我们还将分析从Witwatersrand大学进行的Novavax赞助试验中收集的样品 通过球粒和TCR序列分析，并确定对调整后亚基的响应如何 疫苗与mRNA疫苗诱导的疫苗不同 目标2：评估菌群对抗原特异性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主要T细胞反应的影响 疫苗接种。特别是，我们将分析对此做出反应的TCR曲目和表型 疫苗，因为有明确的迹象表明微生物组会影响T细胞表型，而我们 假设也可能会对曲目产生影响。