Project 2: Immune Response Analysis

项目2：免疫反应分析

• 批准号: 10725054
• 负责人: Bryan Briney
• 金额: $ 51.05万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725054
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Adult; Affinity; Animal Model; Antibodies; Antigens; B-Lymphocytes; Bar Codes; Bioinformatics; Cells; Classification; Clinical Trials; Development; Ensure; Epitope Mapping; Epitopes; Evaluation; Feedback; Genetic; Goals; HIV; HIV vaccine; Human; Immune; Immune response; Immunity; Immunization; Immunize; Immunoglobulin Class Switching; Knock-in Mouse; Leukapheresis; Mission; Modernization; Monoclonal Antibodies; Pattern; Phenotype; Process; Proteomics; Resolution; Resources; Sampling; Series; Specificity; Speed; Techniques; Technology; Testing; Time; Vaccine Design; Vaccines; Visualization software; cohort; cross reactivity; data integration; data management; data sharing; design; experimental study; genetic analysis; humanized mouse; immunogenicity; improved; informatics tool; mouse model; multiple omics; neutralizing antibody; novel; pandemic disease; parallelization; response; success; time interval; time use; vaccine development; vaccine evaluation

PROJECT SUMMARY The purpose of this Project is to apply advanced multi-omics techniques to comprehensively analyze humoral immune responses to promising HIV vaccine immunogens. Our mission is to advance vaccine development by extracting as much information as possible from each immunization trial to best inform the optimal design, composition and delivery of a cohesive immunogen matrix that reliably induces broad, protective HIV immunity. We have devised three Specific Aims which outline the steps necessary to accomplish these goals. Successful completion of these Aims will require indispensable contributions from every component of the MOVE Consortium. In Aim 1, we will deeply characterize the immune response to priming immunogens designed to activate bnAb precursors of one or more specificities (Project 1). While many aspects of this Aim are designed to evaluate the extent to which immunogens are working as designed, equally important is identifying specific genetic and structural features which need improvement during subsequent rounds of refinement and re- evaluation (Structural Proteomics Core). In Aim 2, we will evaluate the human immunogenicity of candidate priming immunogens by isolating immunogen-specific mAbs from HIV-naive humans. This is a critically important aspect of our vaccine development process, as these mAbs are most accurate representation, short of a human clinical trial, of the humoral immune response that will be triggered in actual human vaccine recipients. These mAbs will also be used to create humanized animal models for more thorough vaccine evaluation (Animal Models Core). In Aim 3, we will use our single cell immune multi-omics platform to rapidly evaluate the immune response to sequential vaccine immunogens in near real-time, using the resulting B cell profiles of specificity and function to inform selection of optimal candidates for subsequent boosts. Seamless data sharing between MOVE components and sophisticated tools for visualization and analysis (Data Management & Bioinformatics Core) will allow these analyses to occur within the normal time interval between sequential immunizations. We can then dynamically adjust the parameters of each immunization experiment to maximize our likelihood of success by focusing our experimental resources on the most promising immunogen designs.

项目概要 该项目的目的是应用先进的多组学技术来全面分析体液 对有前途的艾滋病毒疫苗免疫原的免疫反应。我们的使命是通过以下方式推进疫苗开发 从每次免疫试验中提取尽可能多的信息，以便最好地为最佳设计提供信息， 粘性免疫原基质的组成和递送，能够可靠地诱导广泛的、保护性的艾滋病毒免疫。 我们制定了三个具体目标，概述了实现这些目标所需的步骤。成功的 完成这些目标需要 MOVE 各个组成部分做出不可或缺的贡献 财团。在目标 1 中，我们将深入描述针对启动免疫原的免疫反应，该免疫原旨在 激活一种或多种特异性的 bnAb 前体（项目 1）。虽然这个目标的许多方面都是设计的 为了评估免疫原按设计发挥作用的程度，同样重要的是确定特定的免疫原 遗传和结构特征需要在后续几轮细化和重新设计中加以改进 评估（结构蛋白质组学核心）。在目标 2 中，我们将评估候选药物的人类免疫原性 通过从 HIV 感染者中分离出免疫原特异性单克隆抗体来启动免疫原。这是一个批判性的 我们疫苗开发过程的一个重要方面，因为这些单克隆抗体是最准确的代表，简短 人体临床试验，实际人类疫苗中将引发的体液免疫反应 收件人。这些单克隆抗体还将用于创建人源化动物模型，以实现更彻底的疫苗接种 评估（动物模型核心）。在目标 3 中，我们将利用我们的单细胞免疫多组学平台快速 使用所得 B 细胞近乎实时地评估对连续疫苗免疫原的免疫反应 特异性和功能的概况，以告知选择后续增强的最佳候选者。无缝的 MOVE 组件和复杂的可视化和分析工具之间的数据共享（数据 管理和生物信息学核心）将允许这些分析在正常时间间隔内进行 连续免疫之间。然后我们就可以动态调整每次免疫的参数 通过将我们的实验资源集中在最重要的方面来进行实验，以最大限度地提高成功的可能性 有前途的免疫原设计。