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: 10617381
• 负责人: Raiees Ahmad Andrabi
• 金额: $ 13.34万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617381
• 关键词: Address; Affinity; Antibodies; Antibody Affinity; Antibody Response; Antigens; Apical; Automobile Driving; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Biological Models; Biology; Cell Lineage; Consensus; Development; Directed Molecular Evolution; Elements; Engineering; Epitopes; Exclusion; Exhibits; Failure; Genes; Grant; HIV; HIV Infections; HIV envelope protein; HIV vaccine; HIV-1; HIV-1 vaccine; Health; Human; Immunization; Immunoglobulin Gene Rearrangement; Immunoglobulin Somatic Hypermutation; In Vitro; Infection; Intervention; Laboratories; Light; Macaca mulatta; Methods; Molecular; Molecular Conformation; Pan Genus; Peptides; Phase; Polishes; Polysaccharides; Process; Property; Proteins; Regimen; Research Design; Rhesus; SIV; Scheme; Site; Structure; Surface; T cell response; Testing; Time; Translating; Vaccination; Vaccine Design; Vaccine Research; Vaccines; Variant; Virus Replication; Work; cross reactivity; in vivo; nanoparticle; neutralizing antibody; next generation sequencing; novel; novel strategies; preclinical trial; prevent; programs; response; simian human immunodeficiency virus; tool; vaccination strategy; vaccine evaluation; vaccine strategy; vaccine trial; vaccine-induced antibodies; virus envelope; welfare

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.

项目总结/摘要： 研制有效的艾滋病毒疫苗仍然是一项重大挑战。HIV疫苗的早期策略 设计旨在引发保护性T细胞应答、非中和抗体、广泛中和抗体 （bnAb），或三者的某种组合，但未能保护免受感染。该基金旨在吸引 通过一种新的策略，结合多种V2顶点bnAb种系前体的引发，免疫聚焦， 增强和分子引导的亲和力成熟。这项研究的设计源于越来越多的共识， 成功的基于bnAb的疫苗的关键要素将是其以下能力：i）有效地激活和扩增多克隆抗体， 罕见的幼稚bnAb编码B细胞前体; ii）免疫聚焦这些B细胞对典型的，保守的 b nAb表位在HIV Env三聚体上并远离脱靶表位;和iii）通过以下方式使该应答亲和力成熟： 一个分子引导的Env-Ab共同进化的过程。本申请中提出的研究设计涉及 bnAb诱导的这三个关键方面中的每一个。重要的是，我们提出靶向V2顶点bnAb 由于其独特的脆弱性，使其成为bnAb的目标， 超突变和亲和力成熟，没有V-基因插入或缺失，对 特定的轻链配对。因此，我们的建议在其他HIV-1疫苗中是独一无二的。 靶向相对更具挑战性的bnAb靶点（如CD 4 bs、V3-聚糖补丁、融合蛋白）的程序 肽或MPER。该项目包括三个目标：目标#1将分离HIV包膜V2-顶点位点bnAb， CAP256.SU Env SHIV（猴-人免疫缺陷病毒）感染的RM，鉴定其未突变的共同 通过Next-Gen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宽度的CAP 256.SU“Env免疫型”。目标2 将开发CAP 256.SU三聚体免疫原，其表现出对V2顶点bnAb UCA的增强的亲和力， 靶向多种恒河猴和人V2 apex bnAb UCA的体外定向反向疫苗工程。我们 将验证该优化的CAP256.SU GT-三聚体的原生配置，并将其制备为可溶性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稀有V2-apex bnAb B细胞的引发剂 远交RM的前体。目的#3将研究一种基于B细胞谱系的初免-加强免疫策略， RM通过合理工程化的Env三聚体蛋白免疫诱导V2-apex bnAb应答。小说 该疫苗接种方案的方面将是HIV-1 Env SOSIP引发剂，其激活多个生殖系前体 B细胞;使用MT 145 KdV 5 SOSIP Env（一种猴免疫缺陷病毒Env）的V2顶点免疫聚焦加强 来自黑猩猩，其在V2顶点C-链表位中保留与HIV-1的选择性抗原交叉反应性，和 用Env SOSIP三聚体进行“抛光”免疫，所述三聚体对应于来自Env的亲和力分级的V2顶点抗原。 来自SHIV.CAP256.SU感染RM的Ab共进化分析。这项研究将是同类研究中的第一项，如果 成功地在RM中诱导bnAb，将代表基于谱系的疫苗设计的新范例。