Design and Development of a Pan-betacoronavirus Vaccine

摘要--总体 与SARS-CoV-1和MERS相比，目前的SARS-CoV-2病毒具有高度传播性，迄今已 导致全球超过8500,000起病例，超过1,800,000人死亡。有多种地方病流行的人口 蝙蝠、有中间宿主的啮齿动物、果子狸和穿山甲中的冠状病毒株，以及冠状病毒的能力 对于重组，可以肯定的是，具有感染人类潜力的新冠状病毒将导致未来的人类 大流行。为了集中和综合地解决这个问题，这个由病毒学家、免疫学家、 计算生物学家、结构生物学家、生物物理学家、进化生物学家和传统疫苗专家 将开发泛冠病毒(PanbetaCoV)疫苗，包括MerbecoVirus(2c组)，这导致了 MERS和SarbecoVirus(2b组)，它们引起了SARS CoV-1和SARS CoV-2，这三种最致命的病毒 贝塔冠状病毒人类暴发。这笔赠款的意义在于，它将为未来的泛美冠状病毒疫苗提供资金。 在贝塔冠状病毒大流行开始时可以立即获得的流行病，避免了大部分人类 大流行造成的悲剧和社会混乱。P01的总体具体目标是： 目的1.制备并鉴定潘贝塔冠状病毒(2b组)候选疫苗的免疫原性。 目的2.确定2b组疫苗候选疫苗对2b组病毒的保护能力。 目的：研制潘贝塔柯萨奇病毒(PanbetaCoVMerbecVirus，G2c)候选疫苗，测定其免疫原性、交叉免疫原性和免疫原性。 与其他BetaCov的反应性和对2c组病毒的保护能力。 该计划项目赠款包括四个项目。项目1将设计甲型病毒复制子颗粒疫苗 (VRP)疫苗系统，在其独特的小鼠冠状病毒挑战模型中开发和测试P01疫苗。项目2 将使用基于结构的分子建模以及单体和多聚体纳米颗粒尖峰蛋白的设计和 在野生型小鼠模型上进行测试。项目3将设计冠状病毒疫苗和测试疫苗设计，表达为 液体纳米粒(LNPs)中的mRNA。项目4将计算设计B和T细胞泛冠状病毒疫苗。 这份P01提出了三个核心：行政核心，生物遏制和免疫监测核心， 和一个非人类的灵长类核心。P01中的工作将提供PanbetaCoV疫苗以防止逃逸 目前流行的SARS-CoV-2的变种，并将可用于保护社会免受新的BetaCov的影响 未来可能会出现感染人类的病毒。

Abstract - Overall Compared to SARS-CoV-1 and MERS, the current SARS-CoV-2 virus is highly transmissible and to date has caused over 85,000,000cases worldwidewith over 1,800,000 deaths. With an endemic population of multipleother strains of CoVs in bats, rodents with intermediate hosts, civets and pangolins, and because of the ability of CoVs to recombine, it is a certainty that new CoVs with infectious potential for humans will cause future human pandemics. To address this problem in a focused and integrated way, this P01 team of virologists, immunologists, computational biologists, structural biologists, biophysicists, evolutionary biologists, and traditional vacci nologists will develop panbetacoronavirus (panbetaCoV) vaccines, including Merbecoviruses (group 2c), which gave rise to MERS, and Sarbecoviruses (group 2b), which gave rise to SARS CoV-1 and SARS CoV-2, the three most deadly betaCoV human outbreaks. The Significance of this grant is that it will provide for panbetaCoV vaccines for future epidemics that can be immediately available at the onset of a betaCoV pandemic, avoiding much of the human tragedy and social disruption caused by a pandemic. The Overall Specific Aims of the P01 are: Aim 1. Develop and characterize immunogenicity of PanbetaCoV Sarbecovirus (Group 2b) vaccine candidates. Aim 2. Determine Group 2b vaccine candidate protection capacity against group 2b panel of viruses. Aim 3. Develop PanbetaCoVMerbecovirus (group2c) vaccine candidates, determinetheir immunogenicity, cross- reactivity with other betaCoVs and protection capacity against group 2c panel of viruses. This program project grant includes four projects. Project 1 will design vaccines in alphavirus replicon particle (VRP) vaccine system, develop and test P01 vaccines in their unique mouse CoV challenge models. Project 2 will use structure-based molecular modeling and monomer and multimer nanoparticle spike protein designs and test in wild-type mouse models. Project 3 will both design CoV vaccines and test vaccine designs expressed as mRNAs in liquid nanoparticles (LNPs). Project 4 will computationally design B and T cell panbetaCoV vaccines. This P01 proposes three Cores: an Administrative Core, a Biocontainment and Immune Monitoring Core, and a Non-human Primate Core. Work in this P01 will provide panbetaCoV vaccines to protect against escape mutants of SARS-CoV-2 in the current epidemic, and will be available to protect society against new betaCoVs that might emerge to infect humans in the future.