Creating high-resolution, epitope-focused vaccines

项目概要/摘要 本研究的长期目标是建立一种新的方法， 制造疫苗。这些疫苗将导致高度集中的抗体反应， 已知是中和性单克隆抗体靶的特定表位 （mAb）。如果成功，这种方法可以广泛应用于创建重要的，新的 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 产生中和抗体而不是非中和抗体的疫苗。 它还将允许创造疫苗，导致针对 感染因子的高度保守区域，导致广谱保护， 不同的菌株和最小化突变变体"逃逸"的可能性。 该方法的关键起始材料是广泛中和抗 传染源近几十年来，许多有效的、广泛中和的mAb（bnAbs）已经被发现。 被分离出来并详细描述了其中一些bnAb（例如， 流感病毒、埃博拉病毒和HIV-1）已经进入临床试验，以测试它们在治疗 感染性疾病和/或确定被动输注的mAb是否可以预防感染。 然而，尽管有大量的研究资金，但通常不可能制造出疫苗 能够引发具有这些bnAb特性的抗体。 在这里，一个简单但完全不同的方法来创建表位聚焦疫苗， 候选物被利用，其利用了一直沿着可用的工具-mAb本身。 首先，mAb的结合用于保护靶表位。下一个剩余部分的表面 修饰抗原以使其无免疫原性。最后，去除保护性mAb， 从而使未修饰的靶表位脱保护并暴露。这个方法叫做保护， 修饰、去保护（或PMD）。最终，这一高风险、高回报的提议可能会使 产生引发针对任何给定mAb表位的抗体应答的疫苗，并且仅 这个epitope。

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.