Core-002

核心002

• 批准号: 10794904
• 负责人: Richard Thomas Wyatt
• 金额: $ 113.05万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-04 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10794904
• 关键词: Core; 002

Abstract Structure-based vaccine design holds great promise for combatting viral pathogens that create substantial burdens on global health. For HIV, the soluble ectodomain of the envelope glycoprotein (Env), which is the primary target for neutralizing antibody responses, is the focal point for vaccine design. Several different platforms of stable, soluble Env trimers locked in a prefusion, antigenically optimal, conformation are now available and provide the basis for further design efforts. The investigators of this grant developed the native flexibly-linked (NFL) platform, which does not require furin cleavage. The Ward and Wilson labs (Co-PIs of the Structure Core) have shown that NFL trimers adopt native-like structures and the Wyatt lab (Project 1) that they induce neutralizing antibody responses in rabbits and guinea pigs. In fact, a small subset of monoclonal antibodies that have been isolated from these animals show some neutralization breadth, a key next step in trimer-based vaccine design. We have already mapped these antibodies by electron microscopy and showed that one antibody targets an epitope that overlaps with the CD4bs and another targets an epitope near the base of the trimer, similar to some known human broadly neutralizing antibodies. These desirable immune responses are relatively infrequent, but show the promise of these trimer-based immunogens. Based on new structural information and the desire to improve the antigenicity and immunogenicity, further NFL trimers are continually being redesigned. For example, the NFL platform has been elaborated to include the MPER as well as a glycan-depleted version that increases accessibility of the CD4bs, and has been successfully been incorporated into liposomes for multivalent presentation. Each new design was enabled by the available structural information. Hence, this core will continue to provide the necessary structural information to drive Env trimer vaccine innovation in an iterative manner, at the front-end aiding in the design of new immunogens (with Project 1), in the middle by informing boosting strategies using our EM serum profiling analysis (with Project 2), and at the back-end by evaluating the antibody responses to such immunogens at low and high resolution (with Project 2).

抽象的 基于结构的疫苗设计对于对抗病毒病原体具有巨大的希望，这些病原体会产生大量的病毒 全球健康的负担。对于 HIV，包膜糖蛋白 (Env) 的可溶性胞外域是 中和抗体反应的主要目标是疫苗设计的焦点。几种不同的 稳定、可溶性 Env 三聚体平台锁定在预融合、抗原最佳、构象中 并为进一步的设计工作提供基础。这笔赠款的研究人员开发了本地 柔性连接（NFL）平台，不需要弗林蛋白酶切割。沃德和威尔逊实验室（Co-PIs） Structure Core）已表明 NFL 三聚体采用类似天然的结构，并且 Wyatt 实验室（项目 1）表明它们 诱导兔子和豚鼠的中和抗体反应。事实上，单克隆抗体的一小部分 从这些动物中分离出的抗体显示出一定的中和广度，这是下一步的关键 基于三聚体的疫苗设计。我们已经通过电子显微镜绘制了这些抗体的图谱并显示 一种抗体针对与 CD4b 重叠的表位，另一种抗体针对碱基附近的表位 三聚体的结构，类似于一些已知的人类广泛中和抗体。这些理想的免疫反应 相对罕见，但显示了这些基于三聚体的免疫原的前景。基于新结构 信息和提高抗原性和免疫原性的愿望，进一步的 NFL 三聚体不断 正在重新设计。例如，NFL 平台经过精心设计，包括 MPER 以及可增加 CD4b 的可及性的聚糖耗尽版本，并已成功纳入 用于多价呈递的脂质体。每个新设计都是通过可用的结构信息来实现的。 因此，该核心将继续提供必要的结构信息来驱动Env三聚体疫苗 以迭代方式进行创新，在前端协助设计新的免疫原（使用项目 1）， 中间通过使用我们的 EM 血清分析分析（与项目 2）告知加强策略，并在 通过以低分辨率和高分辨率评估抗体对此类免疫原的反应（使用项目 2）。