Project 2: Structure-based antigen and nanoparticle vaccine design

项目2：基于结构的抗原和纳米颗粒疫苗设计

• 批准号: 10425031
• 负责人: Neil King
• 金额: $ 79.3万
• 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/10425031
• 关键词: 2019-nCoV; Achievement; Antibody Response; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Biophysics; COVID-19 pandemic; COVID-19 vaccine; Computing Methodologies; Coronavirus; Data; Development; Epitopes; Evolution; Fc Receptor; Funding; Glycoproteins; Goals; Human; Immune response; Immunity; Immunization; Influenza; Lead; Merbecovirus; Methods; Molecular Conformation; Mosaicism; Mus; Mutation; Performance; Phase; Phase I/II Clinical Trial; Phylogeny; Polysaccharides; Positioning Attribute; Production; Proteins; Sarbecovirus; Science; Secure; Structure; Vaccine Design; Vaccines; Variant; Viral; Work; base; betacoronavirus; betacoronavirus vaccine; biophysical properties; clinical development; computational pipelines; coronavirus receptor; coronavirus vaccine; design; experience; influenza virus vaccine; influenzavirus; lead candidate; mutation screening; nanoparticle; next generation; nonhuman primate; novel; pandemic disease; preclinical development; programs; prototype; receptor binding; response; scaffold; vaccine candidate; virology

PROJECT SUMMARY – PROJECT 2: Structure-based antigen and nanoparticle vaccine design Project 2 is focused on the design, production, and characterization of novel stabilized antigens and broadly protective nanoparticle vaccines. In Aim 1, we will establish automated computational pipelines that identify sets of novel prefusion-stabilizing mutations in the spike proteins of various sarbecovirus, merbecovirus, and embecovirus strains we will use in our broadly protective vaccines. Our recent work has also demonstrated the utility of using deep mutational scanning data to guide the identification of stabilizing mutations in isolated SARS-CoV-2 receptor-binding domains (RBD). The computational pipelines we develop will extend this method to the design of additional stabilized RBD antigens across all four known clades of sarbecoviruses for use in pan-sarbecovirus vaccines. In Aim 2, we will computationally design novel self-assembling protein nanoparticle scaffolds that present prefusion spike trimers in arrays specifically designed to allow unconstrained B cell receptor/antibody access to broadly conserved epitopes. We hypothesize that these scaffolds will elicit antibody responses with superior protective breadth, particularly when used as the basis for mosaic nanoparticle immunogens. We will experimentally validate several novel nanoparticles and prototype their functional performance as monovalent nanoparticle immunogens in immunization and challenge studies in mice to identify the scaffolds that best focus the humoral immune response on conserved epitopes. In Aim 3 we will build on our recent work demonstrating the elicitation of broadly protective immune responses against influenza by generating multivalent nanoparticle vaccines displaying multiple coronavirus RBDs or prefusion spikes. We will take a hierarchical, phylogeny-driven approach. We will focus at first on developing a pan-sarbecovirus vaccine, which will display multiple RBD or prefusion spike antigens. We will then generate broadly protective merbecovirus and embecovirus vaccines displaying multiple prefusion spikes. Finally, we will define the optimal composition of a pan-betacoronavirus nanoparticle vaccine. We will work closely with the other groups in our Program to identify lead pan-sarbecovirus and pan-betacoronavirus vaccine candidates for further preclinical and clinical development at the end of Years 2 and 5 of our Program, respectively.

项目摘要 – 项目 2：基于结构的抗原和纳米颗粒疫苗设计 项目 2 专注于新型稳定抗原的设计、生产和表征，并广泛 保护性纳米颗粒疫苗。在目标 1 中，我们将建立自动化计算管道来识别 各种 sarbecovirus、merbecovirus 和 的刺突蛋白中的一组新的融合前稳定突变 我们将在我们的广泛保护性疫苗中使用嵌入病毒株。我们最近的工作还表明 使用深度突变扫描数据来指导分离的稳定突变的识别的效用 SARS-CoV-2 受体结合域 (RBD)。我们开发的计算管道将扩展这一点 设计所有四个已知 sarbecovirus 进化枝的额外稳定 RBD 抗原的方法 用于泛沙病毒疫苗。在目标 2 中，我们将通过计算设计新型自组装蛋白质 纳米颗粒支架，在阵列中呈现预融合尖峰三聚体，专门设计用于允许 不受限制的 B 细胞受体/抗体可接触广泛保守的表位。我们假设这些 支架将引发具有卓越保护广度的抗体反应，特别是当用作 镶嵌纳米颗粒免疫原。我们将通过实验验证几种新型纳米粒子和原型 它们在免疫和攻击研究中作为单价纳米颗粒免疫原的功能表现 在小鼠中鉴定最能将体液免疫反应集中在保守表位上的支架。目标 3 我们将在我们最近的工作的基础上，证明能够引发广泛的保护性免疫反应 通过生成显示多种冠状病毒 RBD 或预融合的多价纳米颗粒疫苗来治疗流感 尖峰。我们将采取分层的、系统发育驱动的方法。我们将首先专注于开发 泛沙病毒疫苗，将显示多种 RBD 或融合前刺突抗原。然后我们将生成 具有广泛保护性的 merbecovirus 和 embecovirus 疫苗显示出多个预输注尖峰。最后，我们将 确定泛β冠状病毒纳米颗粒疫苗的最佳组成。我们将与 我们计划中的其他小组旨在确定主要的泛 sarbecovirus 和 pan-betacoronavirus 候选疫苗 分别在我们计划的第二年和第五年结束时进行进一步的临床前和临床开发。