Project 2. Animal studies to elucidate the optimal sequence of Env immunogens for induction of distal MPER bnAbs

项目 2. 阐明用于诱导远端 MPER bnAb 的 Env 免疫原最佳序列的动物研究

• 批准号: 10597100
• 负责人: S. Munir ALAM
• 金额: $ 51.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-09 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597100
• 关键词: Affinity; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Response; Antigen Receptors; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Cell Lineage; Detection; Development; Distal; Epitopes; Genealogy; Goals; HIV; HIV Antibodies; HIV envelope protein; HIV-1; Human; Immunization; Immunize; Immunobiology; Immunology; Knock-in Mouse; Laboratories; Macaca; Macaca mulatta; Medicine; Membrane; Mutation; Positioning Attribute; Process; Property; Reagent; Regimen; Research Personnel; Resources; Somatic Mutation; Specificity; Testing; Vaccination; Vaccine Design; Vaccines; Work; biophysical properties; computerized tools; design; immunogenic; immunogenicity; improved; iterative design; member; mouse model; neutralizing antibody; new technology; novel; novel strategies; professor; programs; prototype; synergism; vaccine candidate; vaccine development; vaccine strategy

The recent isolation of several key broad neutralizing antibodies (bnAb) from HIV infected subjects have set the stage for the development of novel strategies for the induction of similar classes of vaccine induced neutralizing antibody responses. Among these recent bnAb isolates, both 10E8 and DH511 target the distal MPER epitopes on HIV Envelope (Env) gp41. Structural and functional analysis of DH511 lineage antibodies have shown that distal MPER epitope bnAbs are among the most broad and potent HIV neutralizing antibodies, thus establishing them as important for vaccine design. For immunogen design, we will partner with the Scripps team in Project 1, and use our new computational program, Antigen Receptor Mutation Analyzer for Detection of Low Likelihood Occurrences (ARMADiLLO), that allows for definition of the critical antibody somatic mutations to be induced, to determine the key IAs that a successful vaccine will need to target. The use of KI mouse models bearing BCR of BnAbs and their UCAs (Unmutated Common Ancestor) has been a major advance that will allow the optimization of unmutated precusor-targeting sequential immunogens, and allow the course of antibody affinity maturation of candidate immunogens to be followed. We will use the newly isolated DH511 distal MPER bnAb clonal lineage UCA, intermediate antibodies (IAs) and bnAbs as reagents upon which to design sequential immunogens and to test these immunogens in a powerful, new knock-in mouse model of bnAb development developed by the Fred Alt laboratory in the Animal Models Core. Moreover, recent breakthoughs in understanding Rhesus macaque immunobiology has allowed similar HIV neutralizing antibody genealogies to be defined and followed throughout vaccination regimens. Our specific Aims are: Aim 2.1. Define functional improbable intermediate antibody (IA) somatic mutations that a successful vaccine will need to select to lead to bnAb induction. Aim 2.2. Define immunogens derived from Project 1 that activate DH511 unmutated precursors and intermediate antibodies in small animal models and in Rhesus macaques. The studies in Project 2 will synergize with studies in Project 1 and Small Animal Models Core to lead to novel designs of immunogens that will lead to initiation and selection of affinity matured distal MPER bnAbs.

最近从HIV感染受试者中分离出几种主要的广泛中和抗体（BNAB）已设置 开发新型策略的阶段，用于诱导类似类别的疫苗诱导 中和抗体反应。在这些最近的BNAB分离株中，10E8和DH511均针对远端 HIV信封（ENV）GP41上的MPER表位。 DH511谱系抗体的结构和功能分析 已经表明，远端MPer表位BNAB是最广泛，最有效的HIV中和 抗体，从而确定它们对于疫苗设计很重要。对于免疫原设计，我们将与 项目1中的Scripps团队，并使用我们的新计算程序抗原受体突变分析仪 为了检测低似然发生（Armadillo），可以定义临界抗体 要诱导的体细胞突变，以确定成功疫苗需要靶向的关键。这 使用BNAB的BCR及其UCAS（未分离的共同祖先）的使用是一种 将允许优化未分解的前驱动的顺序免疫原子和 允许遵循候选免疫原子的抗体亲和力成熟。我们将使用新的 孤立的DH511远端MPER BNAB克隆谱系UCA，中间抗体（IAS）和BNAB作为试剂 在其中设计顺序免疫原并在功能强大的新敲入中测试这些免疫原子 Fred Alt实验室在动物模型核心中开发的BNAB开发的小鼠模型。 此外，最近在理解恒河猴免疫生物学方面的突破已经允许类似的艾滋病毒 中和抗体家谱要定义并遵循整个疫苗接种方案。我们的具体 目的是： 目标2.1。定义成功疫苗的功能性不可能的中间抗体（IA）体细胞突变 将需要选择导致BNAB诱导。 目标2.2。定义从项目1衍生的免疫原子，该项目1激活DH511未分泌的前体和 小动物模型和恒河猕猴中的中间抗体。 项目2中的研究将与项目1和小型动物模型核心的研究协同作用，从而导致新颖 免疫原子的设计将导致亲和力成熟的远端MPER BNABS的启动和选择。