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.

项目概要-项目2：基于结构的抗原和纳米颗粒疫苗设计 项目2的重点是新型稳定抗原的设计、生产和表征， 保护性纳米颗粒疫苗。在目标1中，我们将建立自动计算管道， 在各种肉瘤病毒、梅尔贝病毒和 我们将在广泛的保护性疫苗中使用的恩贝病毒株。我们最近的工作也表明， 使用深度突变扫描数据来指导分离的突变体中稳定突变的鉴定的效用 SARS-CoV-2受体结合域（RBD）。我们开发的计算管道将扩展这一点 方法来设计另外的稳定的RBD抗原，其跨越所有四种已知的肉瘤病毒分支， 用于泛肉瘤病毒疫苗。在目标2中，我们将通过计算设计新的自组装蛋白质 纳米颗粒支架，其在专门设计的阵列中呈现融合前刺突三聚体， 不受限制的B细胞受体/抗体接近广泛保守的表位。我们假设这些 支架将引发具有上级保护宽度的抗体反应，特别是当用作基础时 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性能 在小鼠中鉴定最能将体液免疫应答集中在保守表位上的支架。在目标3 我们将建立在我们最近的工作，证明了广泛的保护性免疫反应的激发， 通过产生展示多个冠状病毒RBD或预融合的多价纳米颗粒疫苗 刺钉我们将采取一种分层次的、以效率为导向的方法。首先，我们将专注于开发一个 泛肉瘤病毒疫苗，其将展示多种RBD或融合前刺突抗原。然后我们将生成 显示多个融合前尖峰的广泛保护性的麻贝病毒和恩贝病毒疫苗。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正在寻找主要的泛肉瘤病毒和泛β冠状病毒候选疫苗， 分别在我们项目的第2年和第5年结束时进行进一步的临床前和临床开发。