HIV Vaccine Candidate Glycopeptide Immunogens

HIV候选疫苗糖肽免疫原

• 批准号: 9981641
• 负责人: Baptiste Aussedat
• 金额: $ 29.96万
• 依托单位: CHEMITOPE GLYCOPEPTIDE, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-22 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981641
• 关键词: AIDS prevention; Adopted; Affinity; Anti-Retroviral Agents; Antibodies; Antigens; B-Lymphocytes; Binding; CH01; Chemicals; Clinical; Consumption; Cysteine; Disulfides; Drug Costs; Engineering; Epitopes; Frequencies; Generations; Glycopeptides; Glycoproteins; Goals; HIV; HIV vaccine; Human; Immune response; Immunization; Immunoglobulin Variable Region; Induced Mutation; Infection; Knock-in Mouse; Lead; Molecular Conformation; Pattern; Persons; Phase; Polysaccharides; Positioning Attribute; Preparation; Process; Property; Regimen; Series; Structure; Surface Plasmon Resonance; Toxicology; Transgenic Mice; Vaccines; beta pleated sheet; chemical synthesis; clinical candidate; covalent bond; first-in-human; glycosylation; human study; in vivo; innovation; mouse model; neutralizing antibody; nonhuman primate; pre-clinical; prevent; prophylactic; response; success; vaccine candidate; vaccine development

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.

采用包膜糖蛋白（Env）作为免疫原的HIV疫苗尚未实现其最初的承诺， 部分原因是这种方法未能诱导广泛中和抗体（bnAb）应答。我们的关键 创新是同质糖肽免疫原的产生和使用， 对HIV包膜糖蛋白的免疫反应。这些糖肽免疫原将形成 艾滋病疫苗的基础 艾滋病毒通过展示许多表位来逃避中和，这些表位导致体内出现主导的非中和反应。 人类然而，在过去的十年中，数十种广泛中和抗体及其同源表位 已经被发现并严格表征，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了这些发现， 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 并通过显示确定的糖基化模式。因此，我们的免疫原1）通过以下方式集中免疫反应： 以高亲和力结合低频未突变的共同祖先（UCA）前体B细胞，2）引导这些 B细胞向成熟的广度和效力和3）避免建立一个非生产性的免疫反应， 分散注意力的非中和表位以前，我们已经合成了几种候选免疫原， 来自Env的第一和第二可变区，V1V2。我们最新的领先临床前候选产品V1V2 GPd 对推断的UCA和成熟bnAb PG 9和CH 01显示出优异的抗原性。可惜 这种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 这一提议。 在这个项目中，我们将开发候选免疫原糖肽，这些糖肽将是化学稳定的， 在整个疫苗制剂中的抗原性。将开发折叠条件以将每一个糖肽拉入 所需的稳定构象，通过共价键形成锁定。我们将评估可行性， 在CH01 UCA敲入小鼠中最有希望的糖肽构建体，以确定它们是否是可行的疫苗 候选人 目的一：合成一系列线性V1V2糖肽免疫原。 目的II：化学锁定V1V2糖肽免疫原的抗原构象。 目的III：在转基因小鼠模型中启动CH01 UCA B细胞的扩增和成熟。