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.

项目摘要 我们已经证明了最近在设计可以绑定HIV广泛中和的免疫原中的成功 具有高亲和力的抗体（BNAB）前体，在免疫动物中扩展这些B细胞，然后选择钥匙 体内超血对于中和广度的发展至关重要。虽然很有希望，但 进度仅限于沿着长而复杂的进化途径的第一步，因为BNAB通常 具有大量的躯体超名。虽然仅需要这些突变的子集 收集广度，尚不清楚哪些突变代表了Env识别的共同特征 可以用免疫原靶向的不同BNAB谱系。识别中常见的成熟事件 针对相同BNAB表位的多个谱系共享的BNAB开发对 疫苗设计策略针对多种BNAB前体。一旦从各种开始 点可以通过启动免疫剂来参与并扩大，增强免疫原子将需要指导其 成熟以获取广泛认可的组成部分。共享识别功能的标识是 只有通过比较一组针对相同表位的BNAB谱系，才有可能。通过我们的当前 Hivrad，我们已经显示了一种用于免疫原设计的灵长类动物BNAB B细胞谱系的来源。 感染的恒河猕猴（RMS）。我们已经证明，被Shivs感染的六分之一的RMS继续进行 生成BNAB响应。这些反应中有三分之一针对V3-聚糖表位， BNAB针对人类感染的最常见部位。 V3 Glycan BNAB的结构测定 从感染感染的RM中分离出来，发现与人V3 Glycan BNAB相似，表明很棒 V3聚糖表位识别的收敛演化。因此，我们现在有一个可靠诱导V3的系统 可以告知引起靶向V3聚糖表位的BNAB的免疫原子设计的聚糖BNAB。这 项目3的中心假设是，BNAB谱系如何识别V3 Glycan中存在共同点 表位，可以设计免疫原剂来为这些共享识别功能选择，当 在顺序免疫方案中合并将引起bnabs。在AIM 1中，我们将确定常见 SHIV和人类感染诱导的V3 Glycan之间共享的V3 Glycan表位识别机制 使用B细胞谱系跟踪和快速结构的BNAB来定义用于免疫原具的模板 决心。在AIM 2中，我们将设计可以在恒河猴和 人类使用新的设计目标，即首先为具有长CDRH3S的B细胞选择。在AIM 3中，我们将使用病毒 将SHIV感染的猴子的测序作为哺乳动物细胞表面中的Env库变体的来源 设计促进在V3 Glycan BNAB识别中选择共享成熟事件的免疫原分。项目 3将通过在RMS中测试的Prime和增强免疫原子来影响该领域，这将导致疫苗 能够在人类中引起bnabs的候选人。