Creating high-resolution, epitope-focused vaccines

创造高分辨率、针对表位的疫苗

• 批准号: 10818694
• 负责人: PETER S KIM
• 金额: $ 15.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818694
• 关键词: Antibodies; Antibody Response; Antigens; Binding; Clinical Trials; Communicable Diseases; Ebola virus; Epitopes; Escape Mutant; Funding; HIV-1; Infection prevention; Infectious Agent; Methods; Monoclonal Antibodies; Property; Research; Resolution; Surface; Testing; Vaccines; Variant; Work; high reward; high risk; influenzavirus; neutralizing antibody; neutralizing monoclonal antibodies; novel; novel strategies; novel vaccines; prevent; tool; vaccine candidate

PROJECT SUMMARY / ABSTRACT The long-term objective of the research proposed here is to establish a novel method for creating vaccines. These vaccines will lead to a highly focused antibody response toward particular epitopes that are known to be the targets of neutralizing monoclonal antibodies (mAbs). If successful, this approach could be applied broadly for the creation of important, new vaccines that protect against infectious disease. The ability to focus the antibody response toward particular epitopes would permit vaccines to be created that elicit neutralizing antibodies, instead of non-neutralizing antibodies. It would also permit creation of vaccines that lead to an antibody response directed against highly conserved regions of an infectious agent, leading to broad spectrum protection against different strains and minimizing the possibility of “escape” by mutant variants. The key starting material for the approach is a mAb that is broadly neutralizing against the infectious agent. In recent decades, many potent, broadly neutralizing mAbs (bnAbs) have been isolated and characterized in detail. Some of these bnAbs (for example, that target influenza virus, Ebola virus and HIV-1) have entered clinical trials to test their efficacy in treating infectious disease and/or to determine whether passively infused mAb can prevent infection. Despite major research funding, however, it has generally not been possible to create vaccines that are capable of eliciting antibodies with properties such as these bnAbs. Here, a simple but radically different approach for creating epitope-focused vaccine candidates is utilized that leverages a tool that has been available all along – the mAb itself. First, binding of the mAb is used to protect the target epitope. Next the surface of the remainder of the antigen is modified to render it non-immunogenic. Finally, the protecting mAb is removed, thereby deprotecting and exposing the unmodified, target epitope. The method is called protect, modify, deprotect (or PMD). Ultimately, this high-risk, high-reward proposal could enable creation of vaccines that elicit an antibody response against any given mAb epitope, and only that epitope.

项目概要/摘要 这里提出的研究的长期目标是建立一种新方法 这些疫苗将导致高度集中的抗体反应。 已知是中和单克隆抗体靶标的特定表位 如果成功，这种方法可以广泛应用于创造重要的新产品。 预防传染病的疫苗。 将抗体反应集中于特定表位的能力将允许 所研制的疫苗可引发中和抗体，而不是非中和抗体。 它还将允许制造疫苗，从而产生针对该病毒的抗体反应。 传染原的高度保守区域，可提供广谱保护 不同的菌株并最大限度地减少突变体“逃逸”的可能性。 该方法的关键起始材料是一种单克隆抗体，可广泛中和 近几十年来，许多有效的、广泛中和的单克隆抗体 (bnAb) 已被证实。 其中一些 bnAb 已被分离和详细表征（例如，该目标）。 流感病毒、埃博拉病毒和 HIV-1）已进入临床试验，以测试其治疗效果 传染病和/或确定被动注射单克隆抗体是否可以预防感染。 然而，尽管有大量研究资金，但通常不可能研制出疫苗 能够引发具有这些 bnAb 等特性的抗体。 这是一种简单但完全不同的方法来创建针对表位的疫苗 候选药物利用了一直可用的工具——单克隆抗体本身。 首先，mAb 的结合用于保护目标表位，然后是其余部分的表面。 抗原的修饰使其无免疫原性，最后去除保护性单克隆抗体。 去保护并暴露未修饰的靶表位，该方法因此被称为保护。 最终，这个高风险、高回报的提议可以实现。 研制能够引发针对任何给定单克隆抗体表位的抗体反应的疫苗，并且仅 那个表位。