Project 4: Computational panbetaCoV immunogen design

摘要-项目4 SARS-CoV-2是Betacoronavirus（betaCoV）属的一个成员，是第三次重大的人畜共患病爆发， 致病性乙型冠状病毒。我们建议设计疫苗，以促进全球努力， 尽快应对COVID-19大流行，然后在这些设计的基础上创建泛β CoV 可用于快速控制未来冠状病毒人畜共患病爆发的疫苗。为此，我们将 1）设计刺突靶向抗体疫苗，注意随着大流行的进展SARS-CoV-2的演变， 和2）保守区T细胞疫苗设计，以将CD 8 T细胞应答重新聚焦于蛋白质组中 不付出高昂的健身成本就无法逃脱。这些针对大流行性流感疫苗的努力将被用作 基础，以扩大我们的疫苗设计策略，以对抗BetaCoV之间发现的变异性，高度 在蝙蝠种群中发现的多种冠状病毒。根据我们对贝塔冠状病毒的初步研究 序列多样性，我们期望使用计算/生物信息学设计基于三价刺突的疫苗 和结构为基础的战略，以提供保护，对已知范围的多样性，发现在亚属 肉瘤病毒这包括SARS-CoV-1、SARS-CoV-2以及从蝙蝠中分离出的许多相关病毒 还有穿山甲如果成功，这些设计将扩展到包括以下亚属的默贝科病毒 MERS病毒和其他在野生蝙蝠、啮齿动物和牛中发现的相关病毒。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.设计刺突疫苗抗原 优化表位暴露和β CoV多样性覆盖。目标3。设计T细胞疫苗， betaCoV中的保守区域。我们基于刺突的计算疫苗设计将基于我们的结构 B细胞镶嵌策略，并将通过刺突糖蛋白结构和分子动力学建模， 并将整合不同刺突蛋白的比对。使用这种方法，我们将设计一组三价的 最佳地覆盖在蝙蝠中的Sarbecovirus中发现的天然多样性的蛋白质的互补 水库由于我们不能肯定地预测可能引起未来人畜共患病的病毒的抗原谱， 我们提出了一个双管齐下的方法，并将同时探索保守区T细胞策略， 虽然它可能不能阻止感染，但可以大大减轻疾病，降低发病率和 传输我们的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Epigraphs。通过专注于最 由于在betaCoV蛋白质组中存在保守区域，我们可以更容易地覆盖betaCoV的广谱 多样性比在更多样化的穗。

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.