Core C: Viral Evolution

核心 C：病毒式进化

• 批准号: 10425028
• 负责人: Jesse D Bloom
• 金额: $ 122.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425028
• 关键词: 2019-nCoV; ACE2; Affect; Affinity; Amino Acids; Antibodies; Antibody-mediated protection; Antigens; Binding; Biochemical; Cells; Collaborations; Complement; Coronavirus; Data; Engineering; Epitopes; Evolution; Goals; Immunity; Libraries; Maps; Measurement; Measures; Merbecovirus; Monoclonal Antibodies; Mutation; Property; Proteins; Risk; Sarbecovirus; Structure; System; Techniques; Vaccine Design; Vaccines; Variant; Viral; Viral Proteins; Virus; Work; Yeasts; Zoonoses; animal model development; base; betacoronavirus; coronavirus vaccine; design; experimental study; interest; mutant; mutation screening; nanoparticle; neutralizing antibody; neutralizing vaccine; pandemic disease; polyclonal antibody; prospective; receptor; receptor binding; resistance mutation; success; tool; vaccine candidate; virology

PROJECT SUMMARY – CORE C: VIRAL EVOLUTION The Viral Evolution Core will develop tools to inform the engineering of vaccines that broadly target coronaviruses that pose a pandemic risk. To do this, the core will use deep mutational scanning to define the biochemical and functional properties of RBDs and spikes across the full evolutionary span of sarbecoviruses and merbecoviruses, and systematically map how these proteins are targeted by vaccine-elicited antibody immunity. In the first aim, we will measure the receptor-binding properties of all known sarbecovirus and merbecovirus RBDs to identify key strains of interest and inform the development of animal models (Core B: Virology, Baric). In the second aim, we will develop a system to measure how all mutations to the spikes from key strains affect cell entry, thereby identifying functionally constrained epitopes to target with vaccines. In the third aim, we will use the RBD and spike libraries to quantify the binding breadth and robustness to mutations of vaccine elicited monoclonal and polyclonal antibodies, thereby providing direct functional readouts to rapidly assess candidate vaccines and inform their further engineering.

项目概要-核心C：病毒进化 病毒进化核心将开发工具，为广泛靶向的疫苗工程提供信息 造成大流行风险的冠状病毒。为此，核心将使用深度突变扫描来定义 在sarbecoviruses的整个进化过程中RBD和尖峰的生化和功能特性 和merbecoviruses，并系统地绘制这些蛋白质如何被疫苗引发的抗体靶向 免疫力在第一个目标中，我们将测量所有已知的Sarbecovirus的受体结合特性， 用于鉴定感兴趣的关键毒株并为动物模型的开发提供信息（核心B： Virology，Baric）。在第二个目标中，我们将开发一个系统来测量所有突变如何从 关键菌株影响细胞进入，从而鉴定疫苗靶向的功能受限表位。在 第三个目标，我们将使用RBD和spike文库来量化结合宽度和对突变的鲁棒性 的疫苗引起的单克隆和多克隆抗体，从而提供直接的功能读数， 评估候选疫苗并告知其进一步工程。