Combining germline-targeting, B cell immunofocusing and Env-Ab co-evolution strategies to induce HIV Envelope V2-apex broadly neutralizing antibodies

结合种系靶向、B 细胞免疫聚焦和 Env-Ab 共同进化策略来诱导 HIV 包膜 V2-apex 广泛中和抗体

• 批准号: 10380767
• 负责人: Raiees Ahmad Andrabi
• 金额: $ 161.81万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380767
• 关键词: Address; Affinity; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Response; Antigens; Automobile Driving; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Biological Models; Biology; Biomedical Engineering; Cell Lineage; Consensus; Development; Elements; Engineering; Epitopes; Evolution; Exclusion; Exhibits; Failure; Fibrinogen; Grant; HIV; HIV Infections; HIV vaccine; HIV-1; HIV-1 vaccine; Health; Human; Immunize; Immunoglobulin Gene Rearrangement; Immunoglobulin Somatic Hypermutation; Infection; Intervention; Knock-in; Knock-in Mouse; Laboratories; Link; Macaca mulatta; Masks; Molecular; Molecular Conformation; Mutagenesis; Pan Genus; Peptides; Phosphoserine; Polishes; Polysaccharides; Principal Investigator; Process; Property; Proteins; Regimen; Research; Research Design; Rhesus; SIV; Scheme; Science; Site; Structure; Surface; T cell response; Talents; Testing; Time; Translating; Vaccination; Vaccine Design; Vaccine Research; Vaccines; Variant; Virus Replication; Work; aluminum sulfate; arm; base; clinical translation; cross reactivity; design; in vivo; mouse model; nanomolar; nanoparticle; neutralizing antibody; next generation; nonhuman primate; novel; novel strategies; novel vaccines; pre-clinical; preclinical trial; prevent; response; simian human immunodeficiency virus; tool; tool development; vaccine evaluation; vaccine strategy; virtual; welfare

PROJECT SUMMARY/ABSTRACT: The development of an effective HIV vaccine has proven to be a daunting 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. All three approaches have thus far failed to consistently protect nonhuman primates (NHPs) or humans from infection. This grant aims to elicit bnAbs by means of a novel strategy that combines – for the first time – germline-targeting, immunofocusing and molecularly guided affinity maturation. This study design evolves from a growing consensus that critical elements to a successful bnAb-based vaccine will be its ability to efficiently bind and activate rare naïve B cell germline precursors of bnAbs; to immunofocus these B cell responses to canonical, conserved bnAb epitopes on the HIV Env trimer and away from off-target strain specific or trimer base epitopes; and to mature or “polish” this bnAb lineage response by a process of molecularly guided Env-Ab coevolution. The study design proposed in this application addresses each of these three essential requirements as it aims to elicit bnAbs targeting the highly conserved HIV-1 V2-apex site. The principal investigators (Andrabi and Shaw) have assembled a talented collaborating research team with a strong track record of scientific discovery, bioengineering and molecular tool development, including the discovery of V2-apex bnAbs (Burton), development of germline targeted V2 apex immunogens (Andrabi), bioengineering of phosphoserine-linked alum nanoparticle antigen displays (Irvine), discovery of V2- apex immunofocusing chimpanzee simian immunodeficiency viruses (Hahn), creation of CRISPRCas9 knock-in mice (Batista), development of next-generation “designer” SHIVs (Shaw) and preclinical-clinical translation (Dey). The project consists of four aims: Aim #1 will isolate HIV envelope V2-apex targeted bnAbs from SHIV infected rhesus macaques, identify their UCA’s, and generate UCA-expressing knock-in mouse models for vaccine evaluation. Aim #2 will design novel V2-apex germline-targeted and immunofocused SOSIP Env trimer immunogens and by mammalian display saturation mutagenesis and structure-guided design present them as soluble proteins or alum-based nanoparticles for enhanced B cell responses. Aim #3 will optimize germline- targeting and B cell immunofocusing boost strategies in V2-apex bnAb UCA-expressing KI-mice and outbred RMs, and will identify in SOSIP Env primed and SHIV infected RMs, Env “immunotypes” that can drive neutralization breadth. Aim #4 will design and test, first in KI mice and then in a pivotal preclinical trial in RMs, an all-SOSIP Env vaccination regimen designed to prime, boost and affinity-mature bnAb responses in a majority of animals. If successful, this would be the first example of a vaccine regimen that consistently elicits bnAbs in an outbred animal model, and it would represent an important beachhead in HIV-1 vaccine science, one that could be transitioned rapidly by our translational partner into human testing.

项目摘要/摘要： 事实证明，有效的艾滋病毒疫苗的发展是一个艰巨的挑战。艾滋病毒以前的策略 旨在引起受保护的T细胞反应，非中和抗体的疫苗设计，广泛中和 抗体（BNAB）或三种组合。到目前为止，这三种方法都未能始终如一 保护非人类灵长类动物（NHP）或人类免受感染。该赠款旨在通过 首次结合种系靶向，免疫焦点和分子指导的新型策略 亲和力成熟。这项研究设计从越来越多的共识发展为关键要素到成功 基于BNAB bnabs;为了免疫焦点，这些B细胞对规范的响应构成了HIV Env Trimer上的BNAB表位 并远离脱靶特异性或触发底座表位；并成熟或“抛光”这个BNAB血统 通过分子引导的ENV-AB协同进化的响应。该应用中提出的研究设计 解决这三个基本要求中的每一个，旨在引起针对高度保守的BNAB HIV-1 V2-APEX网站。首席调查员（安德拉比和肖）已经组建了一个才华横溢的合作 研究团队具有科学发现，生物工程和分子工具开发的良好记录， 包括发现V2-Apex BNABS（Burton），生殖线的开发靶向V2 Apex免疫原 （Andrabi），磷酸盐连接的明矾纳米粒子抗原显示（IRVINE）的生物工程，发现V2- 顶点免疫焦点simian免疫缺陷病毒（HAHN），CRISPRCAS9敲入的创建 小鼠（Batista），开发下一代“设计师” Shivs（Shaw）和临床前临床翻译 （dey）。该项目由四个目标组成：AIM＃1将从SHIV中隔离HIV INVELOPE V2-APEX目标BNABS 感染恒河猕猴，识别其UCA，并为表达UCA的敲门鼠标模型 疫苗评估。 AIM＃2将设计新颖的V2-Apex系列靶向和免疫焦点的SOSIP env Trimer 免疫原和哺乳动物显示安全性诱变和结构引导设计将其显示为 可溶性蛋白或基于明矾的纳米颗粒，用于增强B细胞反应。 AIM＃3将优化种系 - V2-Apex BNAB表达UCA的Ki-Mice和Berbred中的靶向和B细胞免疫焦点促进策略 RMS，并将在Sosip Enved和Shiv感染的RMS中识别可以驱动的“免疫型” 谈判广度。 AIM＃4将设计和测试，首先是在Ki小鼠中，然后在RMS的关键临床前试验中， 大部分旨在促进，增强和亲和力的BNAB响应的全索环境疫苗接种方案 动物。如果成功，这将是疫苗方案的第一个例子 一种示意动物模型，它将代表HIV-1疫苗科学中的重要海滩黑头，一种 我们的转化伙伴可以迅速过渡到人类测试。