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.

项目摘要/摘要： 有效的艾滋病毒疫苗的发展仍然是一个重大挑战。艾滋病毒疫苗的先前策略 设计旨在引起受保护的T细胞反应，非中和抗体，广泛中和抗体 （bnabs），或三个组合，但未能防止感染。这项赠款旨在引起 BNAB通过一种新型策略，结合了多个V2 Apex BNAB生殖前体的启动，免疫凝聚 增强和分子引导的亲和力成熟。这项研究设计来自越来越多的共识 成功基于BNAB的疫苗的关键要素将是其能力：i）有效激活和扩展多个 罕见的幼稚的BNAB编码B细胞前体； ii）这些B细胞对规范，保守的反应 hiv env trimer上的bnab表位，远离靶向表位； iii）亲和力生成这种响应 分子引导的ENV-AB共同进化过程。此申请地址中提出的研究设计 BNAB启发的这三个关键方面中的每一个。重要的是，我们建议针对V2 Apex BNAB 由于其独特的脆弱性，超级现场使其成为bnabs的目标 超名和亲和力成熟，没有V基因插入或缺失，并且限制更少 特定的轻链配对。因此，我们的建议在其他HIV-1疫苗的星座中是独一无二的 针对挑战BNAB目标的程序，例如CD4B，V3-Glycan补丁，融合 肽或MPER。该项目包括三个目的：目标＃1将从 CAP256.SU ENV SHIV（Simian-Human免疫缺陷病毒）感染的RMS，识别其未分离的常见 祖先（UCA）通过下一代测序通过谱系追踪，并通过ENV-AB共同进化推断 分析CAP256.SU“ ENV免疫型”，以选择亲和力成熟和神经化广度。目标＃2 将开发CAP256.SU Trimer Immunogens，通过采用使用V2 Apex BNAB UCA的增强亲和力 电体的定向反向疫苗工程针对多个恒河猴和人类V2 Apex BNAB UCAS。我们 将验证此优化的CAP256.SU GT-Trimer用于本机配置，并作为可溶性SOSIP进行准备 Trimer和Nanoparpicle-Display的触发触发器作为激活多个稀有V2-Apex BNAB B细胞的素数 杂种RMS中的前体。 AIM＃3将研究基于B细胞谱系的原始促进免疫策略 通过合理设计的Env Trimer蛋白免疫来诱导V2-APEX BNAB响应。小说 该疫苗接种方案的各个方面将是激活多种生殖前体的HIV-1 Env SOSIP Prime B细胞；使用MT145KDV5 SOSIP ENV（SIMIAN免疫缺陷病毒Env Env）的V2 Apex免疫封装的增强 来自黑猩猩，在V2 Apex C链表位中保留与HIV-1选择性抗原交叉反应）和 用Env SOSIP三聚体进行“抛光”免疫抑制，与Env-亲和力分级的V2 Apex抗原相对应 来自SHIV.CAP256.SU感染RMS的AB协同进化分析。这项研究将是同类研究中的第一个，如果 成功的RMS诱导BNAB将代表基于谱系的疫苗设计的新范式。