Core C_Ward

摘要 基于结构的疫苗设计在对抗病毒病原体方面大有可为，这些病原体可以产生大量的 对全球健康造成的负担。对于HIV来说，包膜糖蛋白(Env)的可溶性胞外区，即 中和抗体反应的主要靶点是疫苗设计的重点。几种不同的 稳定的、可溶的环境三聚体平台锁定在预融合中，抗原性最优，现在是 并为进一步的设计工作提供了基础。这笔赠款的调查人员开发了当地人 柔性连接(NFL)平台，不需要呋喃裂解。沃德和威尔逊实验室(The Co-Pis of the Structure Core)已经表明，NFL三聚体采用了类似于本地的结构，而怀亚特实验室(项目1)表明，他们 在兔和豚鼠体内诱导中和抗体反应。事实上，克隆的一小部分 从这些动物身上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。我们已经用电子显微镜绘制了这些抗体的图谱，并显示了 一种抗体以与CD4bs重叠的表位为靶标，另一种抗体以碱基附近的表位为靶标。 类似于一些已知的人类广谱中和抗体。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。基于新的结构 信息和提高抗原性和免疫原性的愿望，进一步的NFL三聚体正在不断 被重新设计。例如，NFL平台已被详细说明，包括MPER以及糖链- 耗尽的版本，增加了CD4B的可访问性，并已成功地并入 用于多价给药的脂质体。每一个新的设计都是由可用的结构信息实现的。 因此，这一核心将继续提供必要的结构信息，以推动Env三聚体疫苗 以迭代方式创新，在前端协助设计新的免疫原(项目1)，在 通过使用我们的EM血清图谱分析(与项目2一起)提供增强策略，并在 通过在低分辨率和高分辨率下评估对这些免疫原的抗体反应(与项目2)，对后端进行评估。

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).