Epitope focusing using structure-based immunogen design approaches

使用基于结构的免疫原设计方法进行表位聚焦

• 批准号: 10229281
• 负责人: Blake Marie Hauser
• 金额: $ 3.8万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229281
• 关键词: Epitope; focusing; using; structure; based

Project Summary/Abstract Since the emergence of the novel severe acute respiratory syndrome virus 2 (SARS-CoV-2) coronavirus, the need for better frameworks to rapidly develop vaccines in response to emerging viral threats, including other coronaviruses of potential pandemic concern, is clear. One approach is to develop an immunogen design platform that leverages the often-conserved interface between viral surface glycoproteins and their host cellular receptor(s). For SARS-CoV-2, elicited antibodies would target the interaction between its “spike” glycoprotein and the human angiotensin-converting enzyme 2 (ACE-2) receptor. Other coronaviruses like SARS-CoV-1 and the common cold-causing NL63 also use ACE-2, thus antibodies that interfere with this conserved interaction might also protect against future novel coronaviruses that also use this receptor. The goal of this proposed work is to use structure-guided, rational design of novel immunogens to focus the immune response to the ACE-2 receptor binding interface of SARS-CoV-2. This may provide a generalizable framework of immunogen design strategies that can be rapidly used to combat novel emerging viruses in the future. I will use the following two design approaches: 1) I will use molecular scaffolds that are structurally homologous to the SARS-CoV-2 receptor binding domain (RBD) and “resurface” them with the ACE-2 receptor binding motif (RBM) from SARS- CoV-2. As a result, the antigenically distinct scaffolds will uniformly present the conserved SARS-CoV-2 RBM and will focus the immune response to the conserved interface. 2) I will use hyperglycosylation to mask immunodominant, non-protective epitopes on the SARS-CoV-2 RBD to direct the immune response to the SARS-CoV-2 RBM. For both approaches, I will analyze the elicited immune response to determine the extent of immune focusing to the SARS-CoV-2 RBM, obtain neutralization profiles and structurally characterize down- selected elicited antibodies. Collectively, these data will provide insight into how masking and resurfacing can determinatively direct the immune response to a conserved viral epitope. While I use SARS-CoV-2 as a model virus, this could provide a vaccine design framework for future viral pathogens with the potential for rapid deployment.

项目概要/摘要 自新型严重急性呼吸综合征病毒 2（SARS-CoV-2）冠状病毒出现以来， 需要更好的框架来快速开发疫苗以应对新出现的病毒威胁，包括其他威胁 显然，一种方法是开发一种免疫原设计。 利用病毒表面糖蛋白与其宿主细胞之间通常保守的界面的平台 对于 SARS-CoV-2，引发的抗体将针对其“刺突”糖蛋白之间的相互作用。 以及人类血管紧张素转换酶 2 (ACE-2) 受体等其他冠状病毒，如 SARS-CoV-1 和 引起普通感冒的 NL63 也使用 ACE-2，因此抗体会干扰这种保守的相互作用 也可能预防未来也使用这种受体的新型冠状病毒，这也是这项工作的目标。 是使用结构引导、合理设计的新型免疫原来集中针对 ACE-2 的免疫反应 SARS-CoV-2 的受体结合界面可能提供免疫原设计的通用框架。 未来我将使用以下两种可快速用于对抗新型病毒的策略。 设计方法：1）我将使用结构与SARS-CoV-2同源的分子支架 受体结合结构域（RBD）并用来自 SARS 的 ACE-2 受体结合基序（RBM）“重新表面”它们 因此，抗原性不同的支架将统一呈现保守的 SARS-CoV-2 RBM。 并将免疫反应集中在保守的界面上 2) 我将使用高糖基化来掩盖。 SARS-CoV-2 RBD 上的免疫显性非保护性表位可引导免疫反应 对于这两种方法，我将分析引发的免疫反应以确定 SARS-CoV-2 RBM 的程度。 免疫聚焦于 SARS-CoV-2 RBM，获得中和谱并从结构上表征下调 总的来说，这些数据将提供关于掩蔽和表面重铺如何发挥作用的见解。 确定性地将免疫反应导向保守的病毒表位，而我使用 SARS-CoV-2 作为模型。 病毒，这可以为未来的病毒病原体提供疫苗设计框架，并有可能快速 部署。