Creating high-resolution, epitope-focused vaccines

项目摘要/摘要 这项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 已知为中和单抗靶标的特定表位 (单抗)。如果成功，这种方法可以广泛应用于创造重要的、新的 预防传染病的疫苗。 将抗体反应集中到特定表位的能力将允许 要创造出能激发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…的抗体反应 感染性病原体的高度保守区域，导致广谱保护 不同的菌株，并最大限度地减少突变变种“逃脱”的可能性。 该方法的关键起始材料是一种广泛中和抗病毒的单抗 感染性病原体。近几十年来，许多有效的、广泛中和的单抗(BNAbs)已经 已被分离并详细描述了其特征。其中一些bNAb(例如，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 和/或确定被动输注单抗是否可以预防感染。 然而，尽管有大量的研究资金，但通常不可能制造出疫苗。 能够激发具有这些性质的抗体，如bNAbs。 在这里，一种简单但完全不同的方法来创造以表位为中心的疫苗 候选者利用一直可用的工具-单抗本身。 首先，mAb的结合用来保护目标表位。接下来是剩余部分的表面 对抗原进行修饰，使其不再具有免疫原性。最后，去除保护性单抗， 从而解除保护并暴露未修饰的目标表位。这种方法被称为保护， 修改、取消保护(或PMD)。最终，这一高风险、高回报的提议可能会使 疫苗的研制能够引起针对任何给定单抗表位的抗体反应，而且只能 那个表位。

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.