Project 4: Computational panbetaCoV immunogen design

项目4：计算panbetaCoV免疫原设计

基本信息

批准号：
10327526
负责人：
Rory Henderson
金额：
$ 186.32万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10327526
关键词：
2019-nCoV Adenovirus Vector Alphavirus Animal Model Animals Antibody Response Antigens B-Lymphocytes Bioinformatics CD8-Positive T-Lymphocytes COVID-19 pandemic COVID-19 vaccine Cattle Cavia Cells Cessation of life Chiroptera Clinical Clinical Trials Conserved Sequence Coronavirus Coronavirus spike protein DNA Development Disease Disease Outbreaks Ebola virus Epidemic Epitopes Escape Mutant Evolution Exercise Family suidae Filovirus Foundations Future Goals HIV Infections HIV Vaccine Trials Network HIV vaccine HIV-1 Hand Human Immune response Infection Influenza Hemagglutinin Knowledge Literature Macaca Macaca mulatta Marburgvirus Mediating Messenger RNA Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modeling Molecular Molecular Conformation Morbidity - disease rate Mosaicism Mus Mutation Pathogenicity Phase Phase III Clinical Trials Play Polysaccharides Polyvalent Vaccine Population Proteins Proteome Replicon Reporting Resistance Rodent Role SARS coronavirus SARS-CoV-2 spike protein Structure Symptoms T cell response T-Lymphocyte Testing Vaccine Antigen Vaccine Design Vaccines Variant Viral Virus Work Zoonoses base betacoronavirus betacoronavirus vaccine combat cost design disorder control efficacy clinical trial expectation experience fitness glycoprotein structure immunogenic member mindfulness nanoparticle neutralizing antibody novel coronavirus novel virus pandemic disease pandemic preparedness protein structure research clinical testing response simulation swine influenza transmission process vaccine candidate vaccine delivery vaccine-induced antibodies zoonotic coronavirus

项目摘要

Abstract - Project 4 SARS-CoV-2, a member of the genus Betacoronavirus (betaCoV), is the third major zoonotic outbreak of a highly pathogenic betaCoV in the last two decades. We propose to design vaccines to contribute to the global effort to counter the COVID-19 pandemic as swiftly as possible, and then to build on these designs to create panbetaCoV vaccines that could be used to rapidly contain outbreaks of future coronavirus zoonoses. To these ends, we will design both 1) Spike-targeted antibody vaccines, mindful of SARS-CoV-2 evolution as the pandemic progresses, and 2) conserved-region T-cell vaccine designs, to refocus CD8 T-cell response to regions in the proteome that cannot escape without a high fitness cost. These efforts toward pandemic vaccines will then be used as a foundation to extend our vaccine design strategies to counter the variability found among BetaCoVs, the highly diverse genus of CoVs that are found in bat populations. Based on our preliminary explorations of BetaCoV sequence diversity, we expect the design of a trivalent Spike-based vaccine using computational/bioinformatic and structure-based strategies to provide protection against the known range of diversity found in the subgenus Sarbecovirus. This includes both SARS-CoV-1, SARS-CoV-2, and the many related viruses isolated from bats and pangolins. If successful, these designs will be extended to cover Merbecovirus the subgenus that includes the MERS virus and other related viruses found in wild bats, rodents and cattle. Our Specific Aims are: Aim 1. Track the evolution of the SARS-CoV-2 during the COVID-19 pandemic. Aim 2. Design Spike vaccine antigens that optimize epitope exposure and betaCoV diversity coverage. Aim 3. Design T cell vaccines utilizing the most conserved regions in betaCoV. Our Spike-based computational vaccine designs will be based on our structural B cell mosaics strategy, and will be informed by Spike glycoprotein structures and molecular dynamic modeling, and will incorporate alignments of diverse Spike proteins. Using this approach we will design a trivalent set of complementary of proteins that optimally covers the natural diversity found among Sarbecoviruses in the bat reservoir. As we cannot predict with certainty the antigenic profile of viruses that may give rise to future zoonoses, we propose a two-pronged approach, and will simultaneously explore a conserved-region T-cell strategy that, although it might not block infection, could substantially mitigate disease, reducing both morbidity and transmission. Our T-cell vaccine designs will optimize the coverage of linear epitopes among BetaCoVs with a trivalent vaccine mix using our computational design strategy called Epigraphs. By focusing on the most conserved regions in the betaCoV proteome, we can more readily cover the broad spectrum of BetaCoVs diversity than in the more diverse Spike.

摘要 - 项目 4 SARS-CoV-2 是乙型冠状病毒 (betaCoV) 属的成员，是第三次重大人畜共患疫情。过去二十年中致病性β冠状病毒。我们建议设计疫苗，为全球努力做出贡献尽快应对 COVID-19 大流行，然后在这些设计的基础上创建 panbetaCoV 可用于快速遏制未来冠状病毒人畜共患病爆发的疫苗。为了这些目的，我们将设计 1) 刺突靶向抗体疫苗，注意随着大流行的进展 SARS-CoV-2 的演变， 2) 保守区域 T 细胞疫苗设计，将 CD8 T 细胞反应重新集中到蛋白质组中的区域没有高健身成本就无法逃脱。这些针对大流行疫苗的努力将被用作基金会扩展我们的疫苗设计策略，以应对 BetaCoV 中发现的变异性，BetaCoV 是高度在蝙蝠种群中发现的不同属的冠状病毒。基于我们对 BetaCoV 的初步探索序列多样性，我们期望使用计算/生物信息学设计基于三价 Spike 的疫苗和基于结构的策略，以针对亚属中发现的已知多样性范围提供保护沙贝克病毒。这包括 SARS-CoV-1、SARS-CoV-2 以及从蝙蝠中分离出的许多相关病毒和穿山甲。如果成功，这些设计将扩展到涵盖 Merbecovirus 亚属，其中包括 MERS 病毒以及在野生蝙蝠、啮齿动物和牛身上发现的其他相关病毒。我们的具体目标是：目标 1。追踪 COVID-19 大流行期间 SARS-CoV-2 的演变。目标 2. 设计 Spike 疫苗抗原优化表位暴露和 betaCoV 多样性覆盖。目标 3. 设计利用最多的 T 细胞疫苗 betaCoV 中的保守区域。我们基于 Spike 的计算疫苗设计将基于我们的结构 B 细胞嵌合策略，并将通过 Spike 糖蛋白结构和分子动力学建模获得信息，并将整合不同 Spike 蛋白的比对。使用这种方法，我们将设计一组三价的蛋白质的互补，最佳地覆盖了蝙蝠中 Sarbecovirus 中发现的自然多样性水库。由于我们无法确定地预测未来可能引起人畜共患病的病毒的抗原特征，我们提出了双管齐下的方法，并将同时探索保守区域 T 细胞策略，虽然它可能无法阻止感染，但可以显着减轻疾病，降低发病率和传播。我们的 T 细胞疫苗设计将优化 BetaCoV 中线性表位的覆盖范围使用我们称为 Epigraphs 的计算设计策略的三价疫苗混合物。通过专注于最 betaCoV 蛋白质组中的保守区域，我们可以更容易地涵盖广泛的 BetaCoV 多样性比 Spike 更加多样化。