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.

项目摘要 - 核心C：病毒进化 病毒演化核心将开发工具，以告知广泛针对的疫苗的工程 冠状病毒构成大流行风险。为此，核心将使用深层突变扫描来定义 RBD的生化和功能特性以及SARBECOVIRASS的完整进化跨度的生化特性 和Merbecoviruse，并系统地绘制这些蛋白如何用疫苗吸收的抗体靶向 免疫。在第一个目标中，我们将测量所有已知SARBECOVIRUS的接收器结合特性， Merbecovirus rbds确定关键的关键菌株并为动物模型的发展提供信息（核心B： 病毒学，巴里克）。在第二个目标中，我们将开发一个系统，以衡量如何从 关键菌株会影响细胞的进入，从而识别用疫苗靶向靶向的功能限制的表位。在 第三目的，我们将使用RBD和SPIKE库来量化突变的结合宽度和鲁棒性 疫苗引起的单克隆和多克隆抗体的疫苗，从而提供直接功能读数 评估候选疫苗并告知其进一步的工程。