Project 4: Computational panbetaCoV immunogen design

项目4：计算panbetaCoV免疫原设计

• 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
• 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

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Betacoronavirus属（Betacov）的成员，是第三次主要的人畜共患爆发 在过去的二十年中，致病性Betacov。我们建议设计疫苗，为全球努力做出贡献 尽可能迅速对抗COVID-19的大流行，然后以这些设计建立以创建PanbetaCov 可以用来快速包含未来冠状病毒动物爆发的疫苗。到这些目的，我们将 设计两个）1）以尖峰为目标的抗体疫苗，随着大流行的进展，请注意SARS-COV-2的进化， 2）保守的区域T细胞疫苗设计，以重新聚焦CD8 T细胞对蛋白质组中区域的反应 没有高健身成本就无法逃脱。这些对流血疫苗的努力将被用作 扩展我们的疫苗设计策略以应对Betacovs之间的可变性的基础，高度 在蝙蝠种群中发现的COV的多样化属。根据我们对Betacov的初步探索 序列多样性，我们期望使用计算/生物学的基于三价尖峰的疫苗设计 以及基于结构的策略，以防止子属中发现的已知多样性范围 SARBECOVIRUS。这同时包括SARS-COV-1，SARS-COV-2和从蝙蝠分离的许多相关病毒 和穿山甲。如果成功，这些设计将被扩展以覆盖Merbecovirus，包括 MERS病毒和其他相关病毒在野生蝙蝠，啮齿动物和牛中发现。我们的具体目的是：目标1。 跟踪在COVID-19大流行期间SARS-COV-2的演变。目标2。设计峰值疫苗抗原 这可以优化表位和Betacov多样性覆盖范围。 AIM 3。使用最多的设计T细胞疫苗 贝塔科夫的保守区域。我们基于尖峰的计算疫苗设计将基于我们的结构 B细胞马赛克策略，将通过尖峰糖蛋白结构和分子动态建模来告知 并将结合各种尖峰蛋白的比对。使用这种方法，我们将设计一组三价 蛋白质的互补性，可以最佳地涵盖蝙蝠中SARBECOVIRES中发现的自然多样性 水库。由于我们无法确定预测的病毒的抗原概况可能会导致未来的人畜共患病， 我们提出了一种两管沟的方法，并将同时探索一种保守的区域T细胞策略，该策略，该策略， 尽管它可能无法阻止感染，但可以大大减轻疾病，降低发病率和 传播。我们的T细胞疫苗设计将优化Betacovs中线性表位的覆盖范围 使用我们的计算设计策略称为题词的三价疫苗混合物。通过关注最多 Betacov蛋白质组中的保守区域，我们可以更容易地覆盖Betacovs 多样性比更多样化的尖峰。