Immunogen design to elicit polyclonal bNAb responses to the V3 glycan supersite

免疫原设计引发对 V3 聚糖超级位点的多克隆 bNAb 反应

• 批准号: 10370985
• 负责人: Kevin Wiehe
• 金额: $ 90.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-07 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370985
• 关键词: Affinity; Animal Model; Animals; Antibodies; Antibody Response; Antigens; B cell repertoire; B-Lymphocytes; Back; Binding; Cell Lineage; Cell surface; Complex; Development; Engineering; Epitopes; Event; Evolution; Genealogy; Goals; HIV; HIV vaccine; HIV-1; Human; Immunization; Immunize; Immunogenetics; Immunoglobulin Somatic Hypermutation; Infection; Libraries; Macaca mulatta; Mammalian Cell; Modeling; Molecular; Monkeys; Mus; Mutation; Pathway interactions; Polysaccharides; Primates; Recording of previous events; Regimen; Rhesus; Site; Source; System; Testing; Vaccine Design; Vaccines; Variant; Viral; Work; design; feature detection; high throughput screening; humanized mouse; mouse model; neutralizing antibody; novel; response; simian human immunodeficiency virus; success; vaccination strategy; vaccine candidate; vaccine development

PROJECT SUMMARY We have demonstrated recent success in designing immunogens that can bind HIV broadly neutralizing antibodies (bNAb) precursors with high affinity, expand these B cells in immunized animals, and select for key somatic hypermutations essential for the development of neutralization breadth. Although promising, the progress has been limited to just the first steps along long and complex evolutionary pathways as bNAbs typically have extensive numbers of somatic hypermutation. While only a subset of these mutations is necessary for acquisition of breadth, it is unclear which mutations represent shared features of Env recognition between different bNAb lineages that can be targeted with immunogens. Identifying the common maturational events in bNAb development shared by multiple lineages that target the same bNAb epitope is of critical importance for vaccine design strategies that target a diverse pool of bNAb precursors. Once lineages from diverse starting points are engaged and expanded with priming immunogens, boosting immunogens will need to direct their maturation to acquire the components of broad recognition. The identification of shared recognition features is only possible by comparing a large set of bNAb lineages that target the same epitope. Through our current HIVRAD, we have shown one source of primate bNAb B cell lineages for immunogen design can be SHIV- infected rhesus macaques (RMs). We have demonstrated that one in six RMs infected by SHIVs have gone on to generate bNAb responses. Over one third of these responses have been targeted to the V3-glycan epitope, the most common site targeted by bNAbs in human infection. Structural determination of a V3 glycan bNAb isolated from a SHIV infected RM revealed striking similarities to a human V3 glycan bNAb indicating remarkable convergent evolution of V3 glycan epitope recognition. Thus, we now have a system for reliably inducing V3 glycan bNAbs that can inform the design of immunogens that elicit bNAbs targeting the V3 glycan epitope. The central hypothesis of Project 3 is that commonalities exist in how bNAb lineages recognize the V3 glycan epitope, and that immunogens can be designed to select for these shared recognition features which when combined in a sequential immunization regimen will elicit bNAbs. In Aim 1, we will identify the common mechanisms of V3 glycan epitope recognition shared between SHIV and human infection-induced V3 glycan bNAbs to define templates for immunogen design using B cell lineage tracing and a rapid structural determination. In Aim 2, we will design immunogens that can prime multiple V3 glycan lineages in rhesus and humans using a novel design goal of selecting first for B cells with long CDRH3s. In Aim 3, we will use viral sequencing of SHIV infected monkeys as a source for Env library variants in mammalian cell surface display to design boosting immunogens that select for shared maturational events in V3 glycan bNAb recognition. Project 3 will impact the field by generating prime and boosting immunogens, tested in RMs, that will lead to vaccine candidates capable of eliciting bNAbs in humans.

项目概要 我们最近在设计能够广泛中和 HIV 的免疫原方面取得了成功 具有高亲和力的抗体（bNAb）前体，在免疫动物中扩增这些 B 细胞，并选择关键的 体细胞超突变对于中和广度的发展至关重要。尽管前景广阔， 与 bNAb 一样，进展仅限于漫长而复杂的进化途径的第一步 具有大量的体细胞超突变。虽然只有这些突变的一个子集是必要的 尽管获得了广度，但尚不清楚哪些突变代表了之间的环境识别的共同特征 可以用免疫原靶向的不同 bNAb 谱系。识别常见的成熟事件 靶向相同 bNAb 表位的多个谱系共享的 bNAb 开发对于 针对多种 bNAb 前体的疫苗设计策略。曾经的血统来自不同的起点 点与启动免疫原接触并扩展，增强免疫原将需要引导它们 成熟以获得广泛认可的组成部分。共享识别特征的识别为 只能通过比较大量针对相同表位的 bNAb 谱系来实现。通过我们目前的 HIVRAD，我们已经证明用于免疫原设计的灵长类 bNAb B 细胞谱系的一种来源可以是 SHIV- 受感染的恒河猴（RM）。我们已经证明，六分之一的感染 SHIV 的 RM 已经继续感染 产生 bNAb 反应。超过三分之一的反应针对 V3-聚糖表位， bNAb 在人类感染中最常见的靶点。 V3 聚糖 bNAb 的结构测定 从感染 SHIV 的 RM 中分离出来的抗体与人类 V3 聚糖 bNAb 具有惊人的相似性，表明显着 V3聚糖表位识别的趋同进化。因此，我们现在有了一个可靠地诱导 V3 的系统 聚糖 bNAb 可以为免疫原的设计提供信息，从而引发针对 V3 聚糖表位的 bNAb。这 项目 3 的中心假设是 bNAb 谱系识别 V3 聚糖的方式存在共性 表位，并且可以设计免疫原来选择这些共享的识别特征，当 与序贯免疫方案组合将引发 bNAb。在目标 1 中，我们将确定共同点 SHIV 和人类感染诱导的 V3 聚糖之间共有的 V3 聚糖表位识别机制 bNAbs 使用 B 细胞谱系追踪和快速结构分析来定义免疫原设计模板 决心。在目标 2 中，我们将设计能够在恒河猴和 人类采用了一种新颖的设计目标，即首先选择具有长 CDRH3 的 B 细胞。在目标 3 中，我们将使用病毒式传播 对感染 SHIV 的猴子进行测序，作为哺乳动物细胞表面展示中 Env 文库变体的来源 设计增强免疫原，选择 V3 聚糖 bNAb 识别中共有的成熟事件。项目 3 将通过产生主要的和增强的免疫原来影响该领域，并在 RM 中进行测试，这将导致疫苗的诞生 能够在人类体内引发 bNAb 的候选者。