Project 4: Computational panbetaCoV immunogen design

摘要-项目4 SARS-CoV-2是贝塔冠状病毒属(BetacoronaVirus，BetaCoV)的一员，是世界上第三次高度流行的人畜共患病 在过去的二十年里，致病性的贝塔冠状病毒。我们建议设计疫苗，为全球努力做出贡献 尽快抗击新冠肺炎大流行，然后在这些设计的基础上创建泛美冠状病毒 可用于迅速遏制未来冠状病毒人畜共患病暴发的疫苗。为此，我们将 考虑到SARS-CoV-2随着大流行的进展而演变，设计两种以尖峰为目标的抗体疫苗， 以及2)保守区T细胞疫苗设计，将CD8 T细胞反应重新聚焦到蛋白质组中 如果没有高昂的健身成本，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，以应对在BetaCov之间发现的变异性，高度 蝙蝠种群中发现的不同的冠状病毒属。基于我们对BetaCoV的初步探索 序列多样性，我们期望利用计算/生物信息学设计一种基于三价尖峰的疫苗 以及基于结构的策略，以针对亚属中发现的已知范围的多样性提供保护 萨贝克病毒。这包括SARS-CoV-1、SARS-CoV-2以及从蝙蝠身上分离出的许多相关病毒 还有穿山甲。如果成功，这些设计将被扩展到包括水母病毒的亚属，包括 在野生蝙蝠、啮齿动物和牛身上发现的MERS病毒和其他相关病毒。我们的具体目标是：目标1。 跟踪新冠肺炎大流行期间SARS-CoV-2的演变。目的2.设计尖峰疫苗抗原 这优化了表位暴露和贝塔冠状病毒多样性覆盖。目标3.设计使用最多的T细胞疫苗 贝塔冠状病毒中的保守区。我们基于Spike的计算疫苗设计将基于我们的结构 B细胞嵌合体策略，并将通过Spike糖蛋白结构和分子动力学模型进行信息传递， 并将整合不同的Spike蛋白的比对。使用这种方法，我们将设计一组三价的 互补的蛋白质，最好地覆盖蝙蝠中发现的肉瘤病毒的自然多样性 水库。由于我们无法确切预测可能导致未来人畜共患病的病毒的抗原性， 我们提出了一个双管齐下的方法，同时将探索一种保守区T细胞策略， 虽然它可能不会阻止感染，但可以大大减轻疾病，降低发病率和 变速箱。我们的T细胞疫苗设计将优化BetaCov中线性表位的覆盖率 三价疫苗混合使用我们的计算设计策略称为Eigraphs。通过专注于最重要的 在贝塔冠状病毒蛋白质组中的保守区，我们可以更容易地覆盖贝塔冠状病毒的广泛谱 多样性，而不是在更加多样化的斯派克。

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.