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.

项目摘要 本项目的目的是应用先进的多组学技术，对体液免疫相关基因进行综合分析， 免疫反应的有前途的艾滋病毒疫苗免疫原。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佳地告知最佳设计， 组合物和递送粘性免疫原基质，其可靠地诱导广泛的保护性HIV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 要实现这些目标，就需要《战略行动计划》的每一个组成部分都做出不可或缺的贡献 财团在目标1中，我们将深入描述对设计用于激发免疫原的免疫应答， 激活一种或多种特异性的bnAb前体（项目1）。虽然这一目标的许多方面都是为了 为了评估免疫原按设计发挥作用的程度，同样重要的是识别特异性抗体。 遗传和结构特征，需要在随后的几轮改进和重新 结构蛋白质组学核心（Structural Proteomics Core）在目的2中，我们将评价候选物的人免疫原性。 通过从未感染HIV的人中分离免疫原特异性mAb来引发免疫原。这是一个批判性的 我们疫苗开发过程的重要方面，因为这些mAb是最准确的代表，短 人类临床试验的结果，以及在实际的人类疫苗中引发的体液免疫反应的结果 受惠人士这些单克隆抗体也将用于建立人源化动物模型，以获得更彻底的疫苗。 评价（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， 使用产生的B细胞，近实时评价对连续疫苗免疫原的免疫应答 特异性和功能的概况，以告知后续增强的最佳候选物的选择。无缝 MOVE组件与用于可视化和分析的复杂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的时间间隔内进行 在连续免疫接种之间。然后我们可以动态调整每个免疫的参数 实验，以最大限度地提高我们的成功的可能性，通过集中我们的实验资源在最 有前途的免疫原设计。