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

• 批准号: 10440768
• 负责人: Laurent Karl Verkoczy
• 金额: $ 95.75万
• 依托单位: APPLIED BIOMEDICAL SCIENCE INSTITUTE
• 依托单位国家: 美国
• 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/10440768
• 关键词: Acquired Immunodeficiency Syndrome; Adoptive Transfer; Animal Model; Antibodies; Antibody Formation; Antigens; B cell repertoire; B-Lymphocytes; Binding Sites; CH01; 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

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.

项目摘要 /摘要 开发有效的HIV-1疫苗仍然是全球健康的重点。广泛中和抗体 （BNABS）预防HIV-1感染的（无法通过疫苗接种引起。原因是bnabs 具有不寻常的特征，尽管广度开发至关重要，但对于疫苗诱导是有问题的。 使这一问题混淆了，缺乏有关哪些功能有问题的信息。根据 我们创建了一系列表达原型BNAB先驱体的敲门型（Ki）小鼠，从而研究了它们 体内成熟。此类研究有助于识别候选BNAB，以供疫苗引起疫苗。 这样的承诺线之一是V2 Apex定向的BNAB集合，CH01-04。我们最近确定了艾滋病毒 信封（Env）稳定触发疫苗方案，可重复引起异源层2 NAB反应 CH01前体（UCA）“仅HC” Ki小鼠，迄今为止最有潜力和一致的血清宽度 半聚体模型。但是，在完全多克隆模型中，即使是单个表位免疫原子也无法引起和 如果在幼稚的曲目中很少见，则扩展相关克隆。确实，BNAB的回答就像我们Ki中引起的那些反应 小鼠在具有完全多克隆曲目的动物模型中无法发展，因为天真的前体频率是 对于简单的抗原来说，太低了，更不用说Env，它影响了许多竞争克隆以外的靶向表位。 但是，当在CH01前体引入CH01前体时，次优而可检测的响应确实会产生 嵌合Ki小鼠中可比的限制频率 这样的阈值可能是一种有效的方法。这是我们假设限制速率的步骤 响应产生是其前体频率对于当前基于ENV的方案的禁止。 该立场的必然是，将它们扩展到激活阈值之上将是有变革的，但是 在现有的ENV免疫抑制之前，需要添加预估定步骤。我们的主要目标是筛选各种 合理选择/设计的非HIV（或非典型艾滋病毒）“预普罗蛋白”，以扩展更大的“代理” CH01型前体通过一种新颖的方法我们称为“代理”，这是基于欺骗的概念 免疫系统引起与功能独立但结构构成的前体具有抗 将位点结合起来，可用于BNAB成熟和功能。在AIM 1中，我们将基因确定 允许ENV方案诱导V2 Apex-的收敛前体数量最少（“ CH01代理”） 定向广度。在AIM 2中，我们将测试新颖的“ pre-Proimogens”，以预先扩展限制数字的能力 CH01代理同时测试了各种小说Envs的广度引起的潜力（或其他 启动免疫剂）设计为更具体地针对它们。最后，在AIM 3中，我们将确定“ CH01 在候选者膨胀之前和之后，多克隆，人Ig三角小鼠的代理频率 Primogen/Env组合。这些研究将告知如何进行亚抑制疫苗反应， 特别是那些需要非典型的AB组合区域的其他被遮挡的Env网站（或病原体）。