Design and evaluation of pan-CoV vaccines

泛冠状病毒疫苗的设计和评估

• 批准号: 10841733
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 281.95万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10841733
• 关键词: 2019-nCoV; Amino Acids; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antigens; B-Lymphocytes; Chicago; Chimera organism; Collaborations; Complex; Coronavirus; Coronavirus spike protein; Cryoelectron Microscopy; Data; Development; Encapsulated; Enterobacteria phage MS2; Epitopes; Evaluation; Funding Opportunities; Goals; Head; Hearing; Human; Immune; Immune response; Immune system; Immunization; Immunize; Immunodominant Epitopes; Immunology; Individual; Influenza Hemagglutinin; Japan; Laboratories; Mesocricetus auratus; Messenger RNA; Modification; Molecular Virology; Mus; Mutation; Pharmacologic Substance; Phase I Clinical Trials; Polysaccharides; Positioning Attribute; Pre-Clinical Model; Proteins; Research Project Grants; SARS-CoV-2 spike protein; Saint Jude Children' s Research Hospital; Sampling; Structural Biologist; System; T cell response; T-Lymphocyte; Testing; Universities; Vaccinated; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral Antigens; Virus; Virus-like particle; Wisconsin; X-Ray Crystallography; candidate selection; comparison control; coronavirus vaccine; cross reactivity; design; flexibility; immunogenicity; influenza virus vaccine; influenzavirus; lipid nanoparticle; mutant; nanobiotechnology; novel; novel coronavirus; progenitor; protective efficacy; reconstruction; self assembly; stem; universal coronavirus vaccine; vaccine candidate; vaccine development; vaccine platform; virology

SUMMARY As part of the Pan-Coronavirus Vaccine (PanCoVac) Consortium, the goal of Research Project 1 (RP1) is the ‘Design and evaluation of pan-CoV vaccines’. A comprehensive characterization of the B and T cell responses to vaccination will be carried out by Research Project 2 (RP2, ‘Immunological responses to pan-CoV vaccines. In Aim 1 of RP1 (‘Focusing immune responses towards the stem of the spike protein’), several strategies will be tested to increase the levels of antibodies directed at the conserved, immune-subdominant epitopes in the stem of the SARS-CoV-2 spike protein (to major viral antigen), while avoiding strong antibody responses directed at immunodominant epitopes in the head of the spike protein. These strategies include chimeric spikes composed of SARS-CoV-2 immune-subdominant stem epitopes and immunodominant head epitopes of unencountered coronaviruses, ‘outdiluting’ antibody responses to the immunodominant epitopes by using cocktails of spike proteins with multiple mutations in key amino acid positions, glycan-shielding of immunodominant head epitopes, ‘inverted antigens’ in which the spike protein will be presented to the immune system in an inverted orientation (and thus become more accessible), and ‘headless’ spike proteins lacking portions of the immunodominant head epitopes. Some of these approaches may be tested in combination, and may be tested with sequence-optimized stem epitopes based on ancestral reconstruction (a computational approach to deduce the most likely common progenitor sequence). In Aim 2 (‘Eliciting broadly reactive immune responses to the head of the spike protein’), strategies will be tested to direct the immune responses away from the most sequence-diverse epitopes and towards more conserved epitopes in the head. In addition, conserved heard epitopes will be sequenced-optimized to be recognized by cross-protective antibodies. These modifications will be introduced into diverse spike proteins, and vaccine cocktails of diverse, mutant spike proteins will then be tested for their immunogenicity and protective efficacy. All antigens in Aims 1 and 2 will be designed in collaboration with a structural biologist, and for selected antigens and/or antigen/antibody complexes, X-ray crystallography and Cryo-EM will be carried out. In Aim 3 (‘Immunogenicity and protective efficacy of broadly reactive antigens’), the novel vaccinates will be tested in mice for their immunogenicity; samples from vaccinated mice will be provided to RP2 for B and T cell analysis. Selected vaccine candidates (those with broader immune responses) will next be tested in mice and Syrian hamsters for their ability to provide protection against different coronaviruses. For candidate vaccines that provide broad protection (compared to controls), we will also assess the durability of immune responses, and the effect of vaccination on virus transmissibility. Moreover, these vaccinate candidates will be tested in an mRNA lipid nanoparticle vaccine platform provided by Daiichi Sankyo, a pharmaceutical company.

概括 作为泛氧化病毒疫苗（Pancovac）财团的一部分，研究项目1（RP1）的目标是 “ Pan-CoV疫苗的设计和评估”。 B和T细胞的全面表征 对疫苗接种的反应将由研究项目2（RP2，“免疫学反应）对PAN-COV进行 疫苗。在RP1的AIM 1中（“将免疫回报集中在尖峰蛋白的茎上”），几个 将测试策略以提高针对配置的免疫屈服的抗体水平 SARS-COV-2尖峰蛋白（主要病毒抗原）的茎中的表位，同时避免了较强的抗体 针对峰值蛋白头部免疫主流表位的反应。这些策略包括 由SARS-COV-2免疫 - 延伸的茎表位和免疫主导头部组成的嵌合尖峰 未经冠状病毒的表位，对免疫主流表位的“超过”抗体反应 使用在关键氨基酸位置具有多个突变的尖峰蛋白的鸡尾酒 免疫主导的头部表位，“倒抗原”，其中峰值蛋白将呈现给免疫 倒置的系统（从而变得更容易访问），而“无头”尖峰蛋白缺乏 免疫主导头部表位的一部分。其中一些方法可以组合测试，并且 可以基于祖先重建（计算 推断最有可能的常见祖细胞序列的方法）。在AIM 2中（'引起广泛反应性 免疫反应对峰值蛋白的头部），将测试策略以指导免疫反应 远离大多数序列多样性的表位，而朝着更保守的头部降低。此外， 保守的听力表位将被测序优化以通过跨保护抗体识别。这些 修饰将引入潜水员尖峰蛋白和潜水员突变峰的疫苗鸡尾酒 然后，将测试蛋白质的免疫原性和受保护的效率。目标1和2中的所有抗原将是 与结构生物学家合作设计，并为选定的抗原和/或抗原/抗体复合物合作设计 X射线晶体学和冷冻EM将进行。在AIM 3中（免疫原性和受保护的效率 新型疫苗接种物将在小鼠的免疫原性中测试新型疫苗。来自 接种疫苗的小鼠将提供RP2进行B和T细胞分析。选定的疫苗候选者（那些 接下来，更广泛的免疫反应）将在小鼠和叙利亚仓鼠提供保护的能力中进行测试 针对不同的冠状病毒。对于提供广泛保护的候选疫苗（与对照组相比），我们 还将评估免疫反应的耐用性以及疫苗接种对病毒传播的影响。 此外，这些疫苗接种候选者将在提供的mRNA脂质纳米颗粒疫苗平台中进行测试 Daiichi Sankyo，一家制药公司。