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.

项目总结 本项目的目的是应用先进的多组学技术来综合分析体液 对前景看好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 从每个免疫试验中提取尽可能多的信息，以最好地为最佳设计提供信息， 组成和传递具有凝聚力的免疫原基质，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 完成这些目标将需要行动的每一个组成部分做出不可或缺的贡献 财团。在目标1中，我们将深入描述对免疫原的免疫反应 激活一种或多种特性的bNab前体(项目1)。虽然这个目标的许多方面都是设计的 要评估免疫原发挥作用的程度，同样重要的是确定特定的 遗传和结构特征需要在接下来的几轮细化和重新定位中加以改进 评估(结构蛋白质组学核心)。在目标2中，我们将评估候选疫苗的人类免疫原性 通过从未感染艾滋病毒的人中分离免疫原特异性单抗来启动免疫原。这是一次严重的 我们疫苗开发过程的一个重要方面，因为这些单抗是最准确的代表，简而言之 人体临床试验，将在实际的人类疫苗中触发的体液免疫反应 收件人。这些单抗还将被用于创建人性化的动物模型，以获得更全面的疫苗 评估(动物模型核心)。在目标3中，我们将使用我们的单细胞免疫多组学平台来快速 使用生成的B细胞，近乎实时地评估对顺序疫苗免疫原的免疫应答 特异度和功能的概况，以便为随后的强化提供最佳候选选择。无缝连接 移动组件与用于可视化和分析(数据)的复杂工具之间的数据共享 管理和生物信息学核心)将允许在正常时间间隔内进行这些分析 在顺序免疫之间。然后，我们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大限度地提高成功的可能性 前景看好的免疫原设计。