Development of Viral Vaccines against Sarbecoviruses and Merbecoviruses

项目摘要 在过去的二十年里，出现了六种冠状病毒(CoV)，或者扩大了它们的地理范围。这个 对全球影响最大的紧急人类冠状病毒(SARS-CoV-1、SARS-CoV-2和MERS-CoV)属于 冠状病毒科的贝塔冠状病毒属中的萨贝克病毒和梅贝克病毒的亚属。 许多人畜共患病的高危肉瘤病毒和分枝杆菌病毒都有可能发生人类新发事件，因为 它们可以结合人的ACE2和DPP4进入受体，并感染培养中的人细胞。考虑到历史上 冠状病毒的暴发，加上最近出现的SARS-CoV-2及其对 全球健康和经济，迫切需要开发能够广泛保护人类健康的疫苗 现有和未来的肉瘤病毒和分枝病毒。因此，这项P01提案的首要目标是 产生病毒载体疫苗，诱导广泛的交叉保护性体液和细胞免疫 具有大流行潜力的肉芽病毒和汞病毒，特别是那些人畜共患病的高危病毒 出现在人类群体中。项目3将使用项目1和2中的抗原和表位设计，以 创建疫苗平台，产生针对肉瘤病毒的交叉反应免疫反应和 具有大流行潜力的Merbeco病毒。我们将使用几种SPEKE(S)、RBD和非结构蛋白抗原 它可以作为多价制剂的一部分，诱导广泛的B和T细胞免疫。项目3 将对经鼻腔递送的黑猩猩腺病毒载体病毒进行并行和迭代的工程 (乍得)和肌肉注射活的减毒水泡性口炎病毒(VSV)显示或产生 优化的抗原。表现出最大程度和最大免疫反应的抗原和疫苗 交叉反应性(用核心A确定)将在幼稚、病毒免疫和信使核糖核酸免疫的小鼠身上进行测试 为了确定先前对SARS-CoV-2的免疫如何影响更广泛的我们的免疫原性 瞄准冠状病毒疫苗。显示最佳B和T细胞免疫原性的疫苗(广度、大小和 功能)将优先用于核心B的多个肉瘤病毒和仓鼠挑战研究 Merbeco病毒。我们的建议是产品开发的原则证明。我们预计至少会产生 一种诱导对多种令人担忧的冠状病毒产生广谱免疫的疫苗。

Project Summary Over the past twenty years, six coronaviruses (CoV) have emerged or expanded their geographic range. The emergent human CoVs with the greatest global impact (SARS-CoV-1, SARS-CoV-2, and MERS-CoV) belong to the Sarbecovirus and Merbecovirus subgenera within the Betacoronavirus genus of the Coronaviridae family. Many zoonotic high-risk Sarbecoviruses and Merbecoviruses are poised for human emergence events because they can bind human ACE2 and DPP4 entry receptors and infect human cells in culture. Given the historical outbreaks of CoVs, coupled with the recent emergence of SARS-CoV-2 and its destabilizing consequence on global health and economy, there is an urgent need to develop vaccines capable of broad protection against existing and future Sarbecoviruses and Merbecoviruses. Thus, the overarching goal of this P01 proposal is to generate viral-vectored vaccines that induce broad cross-protective humoral and cellular immunity to Sarbecoviruses and Merbecoviruses with pandemic potential, especially those viruses at high risk for zoonotic emergence into human populations. Project 3 will use antigen and epitope designs from Projects 1 and 2 to create vaccine platforms that generate cross-reactive immune responses against Sarbecoviruses and Merbecoviruses with pandemic potential. We will use several spike (S), RBD, and non-structural protein antigens that can be administered as part of a polyvalent formulation to induce broad B and T cell immunity. Project 3 will perform parallel and iterative engineering of an intranasally delivered chimpanzee adenoviral vectored virus (ChAd) and an intramuscularly delivered live-attenuated vesicular-stomatitis virus (VSV) displaying or producing optimized antigens. Antigens and vaccines that show immune responses of the highest magnitude and greatest cross-reactivity (determined with Core A) will be tested in in naïve, virus-immune, and mRNA vaccinated mice to determine how pre-existing immunity to SARS-CoV-2 impacts the immunogenicity of our more broadly targeting CoV vaccines. Vaccines showing optimal B and T cell immunogenicity (breadth, magnitude, and function) will be prioritized for mouse and hamster challenge studies in Core B with multiple Sarbecoviruses and Merbecoviruses. Our proposal is a proof-of-principle for product development. We envision generating at least one vaccine that induces broad-spectrum immunity to multiple CoV of concern.