HIV Vaccine Candidate Glycopeptide Immunogens

使用包膜糖蛋白(Env)作为免疫原的HIV疫苗没有实现最初的承诺，在 部分原因是这种方法未能诱导广谱中和抗体(BNab)反应。我们的钥匙 创新之处在于产生和使用均一糖肽免疫原来发起和聚焦 针对HIV包膜糖蛋白的免疫反应。这些糖肽免疫原将形成 艾滋病毒疫苗的基础。 HIV通过展示许多导致显性非中和反应的表位来逃避中和 人类。然而，在过去的十年里，数十种广谱中和抗体及其同源表位 已经被发现并严格描述了特征，从而为开发潜在的疫苗提供了路线图。 Chemitope生产的糖肽和候选免疫原利用这些发现并忠实地 通过采用靶向结构来模拟这些广泛中和表位的基本结构特征 并通过显示定义的糖基化模式。因此，我们的免疫原通过以下方式集中免疫反应 与低频率未突变的共同祖先(UCA)前体B细胞高亲和力结合，2)引导这些 B细胞走向成熟的广度和效力，以及3)避免建立对 分散注意力的非中和表位。在此之前，我们已经合成了几种候选免疫原源 来自环境蛋白V1V2的第一和第二可变区。我们最新的领先临床前候选V1V2 GPD 对推测的UCA和成熟的bNAbs PG9和CH01表现出良好的抗原性。不幸的是， 该糖肽的抗原构象在体内是不稳定的。解决这种构象不稳定性是重点 这项提议。 在这个项目中，我们将开发具有化学稳定性和保存性的候选免疫原糖肽 在疫苗配方中始终具有抗原性。将开发折叠条件以将每个糖肽吸引到 通过共价键的形成锁定所需的稳定构象。我们将评估我们的可行性 在CH01 UCA基因敲入小鼠中构建最有希望的糖肽以确定它们是否为有效疫苗 候选人。 目的I：合成一系列线性V1V2糖肽免疫原。 目的II：用化学方法将V1V2糖肽免疫原锁定在抗原构象中。 目的III：在转基因小鼠模型中启动CH01UCA B细胞的扩增和成熟。

HIV vaccines employing the Envelope glycoprotein (Env) as an immunogen have not met their initial promise, in part, because this approach has failed to induce a broadly neutralizing antibody (bnAb) response. Our key innovation is the generation and use of homogeneous glycopeptide immunogens to initiate and focus an immune response against the HIV envelope glycoprotein. These glycopeptide immunogens will form the basis of an HIV vaccine. HIV evades neutralization by displaying many epitopes that result in a dominant non-neutralizing response in humans. However, over the last ten years, dozens of broadly neutralizing antibodies and their cognate epitopes have been discovered and rigorously characterized, thus providing a roadmap to develop potential vaccines. The glycopeptides and candidate immunogens produced by Chemitope leverage these discoveries and faithfully mimic the essential structural features of these broadly neutralizing epitopes by adopting the targeted structure and by displaying a defined glycosylation pattern. Therefore, our immunogens 1) focus the immune response by binding with high affinity to low-frequency unmutated common ancestor (UCA) precursor B cells, 2) guide these B cells toward mature breadth and potency and 3) avoid building a non-productive immune response to the distracting, non-neutralizing epitopes. Previously, we have synthesized several candidate immunogens derived from the first and second variable region of Env, V1V2. Our most recent lead pre-clinical candidate V1V2 GPd displays excellent antigenicity toward the inferred UCA and mature bnAbs PG9 and CH01. Unfortunately, the antigenic conformation of this glycopeptide is unstable in vivo. Solving this conformational instability is the focus of this proposal. In this project, we will develop candidate immunogen glycopeptides that will be chemically stable and retain antigenicity throughout vaccine formulation. Folding conditions will be developed to draw each glycopeptide into the desired stable conformation, locked through covalent bond-formation. Feasibility will be evaluated for our most promising glycopeptide constructs in CH01 UCA knock-in mice to determine if they are viable vaccine candidates. Aim I: Synthesize a series of linear V1V2 Glycopeptide Immunogens. Aim II: Chemically lock the V1V2 Glycopeptide Immunogens in the antigenic conformation. Aim III: Initiate the expansion and maturation of CH01 UCA B cells in a transgenic mouse model.