Core C_Ward

核心C_病房

• 批准号: 10339442
• 负责人: Andrew Barrett Ward
• 金额: $ 62.13万
• 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/10339442
• 关键词: 3-Dimensional; Adopted; Animals; Antibodies; Antibody Binding Sites; Antibody Response; Antigen-Antibody Complex; Antigens; B-Lymphocytes; Back; Binding; Biophysics; Cavia; Collaborations; Complex; Cryoelectron Microscopy; Crystallization; Data; Docking; Electron Microscopy; Epitopes; Glycoproteins; Grant; HIV; Human; Image; Immune response; Immunization; Immunize; Individual; Infection; Infrastructure; Link; Liposomes; Manuscripts; Maps; Modeling; Molecular Conformation; Monoclonal Antibodies; Negative Staining; Oryctolagus cuniculus; Polysaccharides; Proteins; Publishing; Research Institute; Research Personnel; Resolution; Roentgen Rays; Serum; Structure; Synchrotrons; Techniques; Technology; Testing; Vaccine Design; Vaccines; Viral Proteins; X-Ray Crystallography; base; beamline; design; flexibility; global health; glycoprotein structure; immunogenicity; improved; innovation; interest; natural antibodies; neutralizing antibody; nonhuman primate; novel; pathogenic virus; polyclonal antibody; prospective; reconstruction; response; ward

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).

摘要 基于结构的疫苗设计对于对抗产生大量病毒的病毒病原体具有很大的希望。 全球健康的负担。对于HIV，包膜糖蛋白（Env）的可溶性胞外域，即 中和抗体应答的主要靶标是疫苗设计的焦点。几种不同 稳定的、可溶性Env三聚体锁定在融合前抗原最佳构象的平台现在已经被开发出来。 并为进一步的设计工作提供基础。这项资助的研究人员开发了 柔性连接（NFL）平台，其不需要弗林蛋白酶裂解。沃德和威尔逊实验室（ 结构核心）已经表明，NFL三聚体采用类似天然的结构和怀亚特实验室（项目1），他们 在兔和豚鼠中诱导中和抗体应答。事实上，一小部分单克隆抗体 已经从这些动物中分离的抗体显示出一定的中和宽度，这是免疫的关键下一步。 三聚体疫苗设计。我们已经通过电子显微镜绘制了这些抗体的图谱， 一种抗体靶向与CD 4 b重叠的表位，另一种靶向靠近碱基的表位， 三聚体，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 是相对罕见的，但显示这些基于三聚体的免疫原的前景。基于新结构 出于信息以及提高抗原性和免疫原性的愿望，进一步的NFL三聚体不断地被 正在重新设计。例如，NFL平台已经被精心设计以包括MPER以及聚糖- 耗尽的版本，增加了CD 4 b的可及性，并已成功地被纳入 脂质体用于多价呈递。每个新的设计都是通过可用的结构信息实现的。 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。 以迭代的方式创新，在前端帮助设计新的免疫原（与项目1）， 通过使用我们的EM血清分析（与项目2一起）告知加强策略，以及 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2一起）。