Novel vaccine strategies to induce V2 apex-directed broad neutralizing antibodies

诱导 V2 顶端定向广泛中和抗体的新疫苗策略

基本信息

批准号：
10467068
负责人：
Laurent Karl Verkoczy
金额：
$ 108.98万
依托单位：
APPLIED BIOMEDICAL SCIENCE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-04 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10467068
关键词：
Acquired Immunodeficiency Syndrome Adoptive Transfer Animal Model Antibodies Antibody Formation Antigens B cell repertoire B-Lymphocytes Binding Sites CH01 precursor Cattle Chimera organism Data Development Engineering Epitopes Exhibits Failure Frequencies Generations Genetic Variation Glycoproteins Goals HIV HIV vaccine HIV-1 HIV-1 vaccine Health Priorities Human Immune system Immunization Individual Infection Knock-in Knock-in Mouse Lead Learning Life Methods Modeling Mus Mutation Plasma Primates Protocols documentation Proxy Rapid screening Regimen Series Serum Site Specificity Structure Testing Time Ursidae Family Vaccinated Vaccination Vaccines Viral base cohort design global health in vivo neutralizing antibody novel novel strategies novel vaccines pandemic disease pathogen pathogenic virus prototype reconstitution response stem trait vaccine response vaccine strategy

项目摘要

PROJECT SUMMARY / ABSTRACT Developing an effective HIV-1 vaccine remains a major global health priority. Broadly neutralizing antibodies (bnAbs) that protect against HIV-1 infection cannot be elicited by vaccination. A reason for this is that bnAbs have unusual features that while critical for breadth development, are problematic for vaccine induction. Confounding this, information regarding which features are problematic for vaccination is lacking. Accordingly, we created a series of knock-in (KI) mice expressing precursors of prototype bnAbs, allowing the study of their in vivo maturation. Such studies have helped in identifying candidate bnAbs more tractable for vaccines to elicit. One such promising lead is the V2 apex-directed set of bnAbs, CH01-04. We recently identified an HIV Envelope (Env) stabilized trimer vaccine regimen that reproducibly elicits heterologous tier 2 nAb responses in CH01 precursor (UCA) “HC only” KI mice, the most potent and consistent serum breadth elicited to date in a semi-polyclonal model. However, in fully polyclonal models, even single epitope immunogens fail to elicit and expand relevant clones if infrequent in the naïve repertoire. Indeed, bnAb responses like those elicited in our KI mice fail to develop in animal models with fully polyclonal repertoires, because naive precursor frequencies are far too low for even simple antigen, let alone Env, which induces many competing clones to off-target epitopes. However, suboptimal yet detectable responses do develop when CH01 precursors are introduced at comparable limiting frequencies in chimeric KI mice, suggesting that devising methods to clonally expand above such thresholds may be an effective approach. Thus, we hypothesize that the rate-limiting step to CH01-type response generation is their precursor frequencies being prohibitively low for current Env-based regimens. The corollary of this posit is that expanding them above activation thresholds would be transformative, but will require adding a pre-priming step, prior to existing Env immunization. Our main objective is to screen various rationally selected/designed non-HIV (or atypical HIV) “pre-primogens”, for the ability to expand a larger “proxy” pool of CH01-type precursors via a novel approach we term “priming by proxy”, a concept based on tricking the immune system into eliciting functionally-independent yet structurally-convergent precursors bearing Ab- combining sites amenable for both bnAb maturation and function. In Aim 1, we will genetically determine the minimal number of convergent precursors (“CH01 proxies”) that permit Env regimens to induce V2 apex- directed breadth. In Aim 2, we will test novel “pre-primogens” for their ability to pre-expand limiting numbers of CH01 proxies, while at the same time, test the breadth-inducing potential of various novel Envs (or other priming immunogens) engineered to more specifically target them. Finally, in Aim 3, we will determine “CH01 proxy” frequencies in polyclonal, human Ig TrianniTM mice before and after expansion with candidate pre- primogen/Env combinations. These studies will inform on how to potentiate subdominant vaccine responses, particularly those to other occluded Env sites (or pathogens), needing atypical Ab-combining regions.

项目概要/摘要开发有效的 HIV-1 疫苗仍然是全球卫生的主要优先事项。 (bnAbs) 不能通过疫苗接种来预防 HIV-1 感染，原因之一是 bnAbs。具有不寻常的特征，虽然对广度发展至关重要，但对疫苗诱导来说却是个问题。令人困惑的是，缺乏关于哪些特征对疫苗接种有问题的信息。我们创建了一系列表达原型 bnAb 前体的敲入 (KI) 小鼠，从而可以研究它们的此类研究有助于确定更易于疫苗诱导的候选 bnAb。其中一个有希望的先导药物是 V2 顶端定向的 bnAb 组，CH01-04，我们最近发现了一种 HIV。包膜 (Env) 稳定的三聚体疫苗方案可重复地引发异源 2 级 nAb 反应 CH01 前体 (UCA)“仅 HC”KI 小鼠，迄今为止在然而，在完全多克隆模型中，即使是单一表位免疫原也无法引发和如果在初始库中不常见，则扩展相关克隆。事实上，bnAb 反应就像我们 KI 中引发的反应一样。小鼠无法在具有完全多克隆库的动物模型中发育，因为幼稚前体频率是即使对于简单的抗原来说，这个值也太低了，更不用说 Env 了，它会诱导许多竞争性克隆产生脱靶表位。然而，当 CH01 前体在以下位置引入时，确实会出现次优但可检测的反应：嵌合 KI 小鼠中具有可比的极限频率，这表明设计克隆扩增方法这样的阈值可能是一种有效的方法，因此，我们采取了CH01型的限速步骤。反应产生的原因是它们的前体频率对于当前基于 Env 的方案来说非常低。这一立场的必然结果是，将它们扩展到激活阈值以上将是变革性的，但也会在现有的环境免疫之前需要添加预启动步骤我们的主要目标是筛选各种。合理选择/设计的非艾滋病毒（或非典型艾滋病毒）“前引发剂”，能够扩大更大的“代理” 通过一种我们称之为“代理启动”的新方法来池化 CH01 型前体，这是一个基于欺骗的概念免疫系统诱导功能独立但结构趋同的带有抗体的前体结合适合 bnAb 成熟和功能的位点在目标 1 中，我们将从基因角度确定允许 Env 方案诱导 V2 顶点的收敛前体（“CH01 代理”）的最小数量在目标 2 中，我们将测试新型“前原原”预扩展有限数量的能力。 CH01 代理同时测试各种新颖环境（或其他环境）的广度诱导潜力最后，在目标 3 中，我们将确定“CH01”。候选预扩增前后多克隆人 Ig TrianniTM 小鼠中的“代理”频率这些研究将揭示如何增强次优势疫苗反应，特别是对于其他封闭的 Env 位点（或病原体），需要非典型的 Ab 组合区域。