B cell lineage directed rational vaccine strategies based on CAP256SU Env-Ab coevolution

基于 CAP256SU Env-Ab 协同进化的 B 细胞谱系定向合理疫苗策略

• 批准号: 10936682
• 负责人: Raiees Ahmad Andrabi
• 金额: $ 74.36万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-04 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10936682
• 关键词: cell; lineage; directed; rational; vaccine

PROJECT SUMMARY/ABSTRACT: The development of an effective HIV vaccine remains a major challenge. Previous strategies for HIV vaccine design aimed to elicit protective T cell responses, non-neutralizing antibodies, broadly neutralizing antibodies (bnAbs), or some combination of the three but have failed to protect against infection. This grant aims to elicit bnAbs by a novel strategy that combines priming of multiple V2 apex bnAb germline precursors, immunofocused boosting, and molecularly-guided affinity-maturation. This study design derives from a growing consensus that critical elements to a successful bnAb-based vaccine will be its ability to: i) efficiently activate and expand multiple rare naïve bnAb-encoding B cell precursors; ii) immunofocus these B cell responses to canonical, conserved bnAb epitopes on the HIV Env trimer and away from off-target epitopes; and iii) affinity-mature this response by a process of molecularly-guided Env-Ab co-evolution. The study design proposed in this application addresses each of these three critical aspects of bnAb elicitation. Importantly, we propose to target the V2 apex bnAb supersite because of its unique vulnerabilities, which allow it to be targeted by bnAbs with less somatic hypermutation and affinity maturation, without V-gene insertions or deletions and with less restriction for particular light chain pairings. Our proposal is thus unique among the constellation of other HIV-1 vaccine programs that target relatively more challenging bnAb targets such as the CD4bs, V3-glycan patch, fusion peptide or MPER. The project includes three aims: Aim #1 will isolate HIV envelope V2-apex site bnAbs from CAP256.SU Env SHIV (simian-human immunodeficiency virus)-infected RMs, identify their unmutated common ancestors (UCAs) through lineage-tracing by Next-Gen sequencing, and infer through Env-Ab co-evolution analyses CAP256.SU “Env immunotypes” that select for affinity-maturation and neutralization breadth. Aim #2 will develop CAP256.SU trimer immunogens that exhibit enhanced affinity for V2 apex bnAb UCAs by employing in-vitro directed reverse vaccine engineering that targets multiple rhesus and human V2 apex bnAb UCAs. We will validate this optimized CAP256.SU GT-trimer for native configuration and prepare it as a soluble SOSIP trimer and nanoparticle-displayed trimer for testing as a prime to activate multiple rare V2-apex bnAb B cell precursors in outbred RMs. Aim #3 will investigate a B cell lineage-based prime-boost immunization strategy in RMs to induce V2-apex bnAb responses by rationally engineered Env trimer protein immunizations. Novel aspects of this vaccination regimen will be an HIV-1 Env SOSIP prime that activates multiple germline precursor B cells; a V2 apex immunofocused boost using MT145KdV5 SOSIP Env (a simian immunodeficiency virus Env from chimpanzees that retains selective antigenic cross-reactivity with HIV-1 in V2 apex C-strand epitopes), and “polishing” immunizations with Env SOSIP trimers corresponding to affinity-graded V2 apex antigens from Env- Ab coevolution analyses from SHIV.CAP256.SU infected RMs. This study will be the first of its kind, and if successful in inducing bnAbs in RMs, would represent a new paradigm for lineage-based vaccine design.

项目概要/摘要： 开发有效的艾滋病毒疫苗仍然是先前艾滋病毒疫苗策略的主要挑战。 设计旨在引发保护性 T 细胞反应、非中和抗体、广泛中和抗体 （bnAbs），或三者的某种组合，但未能防止感染。这项资助旨在引发感染。 bnAb 通过一种新颖的策略结合了多个 V2 顶端 bnAb 种系前体的启动，免疫聚焦 这项研究设计源于越来越多的共识： 基于 bnAb 的疫苗成功的关键要素是其以下能力： i) 有效激活和扩展多个 罕见的幼稚 bnAb 编码 B 细胞前体 ii) 免疫聚焦这些 B 细胞对规范、保守的反应； bnAb 表位位于 HIV Env 三聚体上并远离脱靶表位；以及 iii) 通过以下方式使这种反应亲和力成熟； 本申请提出的研究设计解决了分子引导的 Env-Ab 协同进化过程。 bnAb 诱导的这三个关键方面中的每一个都重要的是，我们建议以 V2 顶端 bnAb 为目标。 supersite 由于其独特的漏洞，使其成为体细胞较少的 bnAb 的目标 超突变和亲和力成熟，无 V 基因插入或缺失，并且对 因此，我们的建议在其他 HIV-1 疫苗中是独一无二的。 针对相对更具挑战性的 bnAb 靶点的计划，例如 CD4bs、V3-聚糖补丁、融合 该项目包括三个目标： 目标#1 将从中分离出 HIV 包膜 V2 顶端位点 bnAb。 CAP256.SU Env SHIV（猿人免疫缺陷病毒）感染的 RM，识别其未突变的共同点 通过下一代测序进行谱系追踪，并通过 Env-Ab 共同进化进行推断 分析选择亲和力成熟和中和广度的 CAP256.SU“Env 免疫类型”目标#2。 将开发 CAP256.SU 三聚体免疫原，通过采用对 V2 apex bnAb UCA 表现出增强的亲和力 针对多种恒河猴和人类 V2 apex bnAb UCA 的体外定向逆向疫苗工程。 将验证此优化的 CAP256.SU GT-三聚体的本机配置并将其准备为可溶性 SOSIP 三聚体和纳米颗粒展示的三聚体，用于测试作为激活多种罕见 V2-apex bnAb B 细胞的原素 目标 #3 将研究基于 B 细胞谱系的初免-加强免疫策略。 RM 通过合理设计的 Env 三聚体蛋白免疫诱导 V2-apex bnAb 反应。 该疫苗接种方案的一个方面是 HIV-1 Env SOSIP 启动，可激活多个种系前体 B 细胞；使用 MT145KdV5 SOSIP Env（一种猿猴免疫缺陷病毒 Env）进行 V2 apex 免疫聚焦增强 来自黑猩猩，在 V2 顶端 C 链表位中保留与 HIV-1 的选择性抗原交叉反应性），以及 使用与来自 Env-的亲和力分级的 V2 顶端抗原相对应的 Env SOSIP 三聚体“抛光”免疫 对 SHIV.CAP256.SU 感染的 RM 进行抗体协同进化分析 这项研究将是此类研究中的第一项。 在 RM 中成功诱导 bnAbs，将代表基于谱系的疫苗设计的新范例。