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 该项目的目的是应用先进的多媒体技术来全面分析体液 免疫反应对有希望的HIV疫苗免疫原子。我们的使命是通过 从每项免疫试验中提取尽可能多的信息，以最佳地为最佳设计提供信息， 可靠地诱导广泛的保护性HIV免疫的内聚免疫基质的组成和递送。 我们设计了三个具体目标，概述了实现这些目标所需的步骤。成功的 这些目标的完成将需要移动的每个组成部分的必要贡献 财团。在AIM 1中，我们将深入描述对启动免疫原的免疫反应 激活一个或多个特异性的BNAB前体（项目1）。虽然该目标的许多方面是设计的 为了评估免疫原子设计的程度，同样重要的是确定特定 遗传和结构特征，在随后的细化和重新进行期间需要改进 评估（结构蛋白质组学核心）。在AIM 2中，我们将评估候选人的人类免疫原性 通过从艾滋病毒的人类中分离免疫原特异性mAb来启动免疫原。这是一个批判性的 疫苗开发过程的重要方面，因为这些mAb是最准确的表示，所以很短 人类临床试验的体液免疫反应将在实际人类疫苗中触发 收件人。这些mAB也将用于创建人源化动物模型，以进行更彻底的疫苗 评估（动物模型核心）。在AIM 3中，我们将使用我们的单细胞免疫多词平台快速 使用所得的B细胞，评估接近实时对顺序疫苗免疫原子的免疫反应 特异性和功能的概况，以告知选择最佳候选者以进行后续提升。无缝的 移动组件和复杂工具之间可视化和分析的数据共享（数据 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个免疫的参数 通过将我们的实验资源重点放在最大化的可能性上，以最大程度地提高我们的成功可能性 有希望的免疫原具。