The Development and Evaluation of Pan-Coronavirus Vaccines

总体摘要 鉴于冠状病毒在历史上的暴发，加上最近出现的SARS- CoV-2和新冠肺炎对全球卫生和经济的不稳定后果，有 迫切需要开发能够广泛保护现有疫苗的新疫苗 以及未来的肉瘤病毒和沙门氏病毒。本P01计划项目(PPG)致力于 假设进化设计和优化的B和T细胞的组合 抗原可以产生广泛和保护性的免疫力来对抗肉瘤病毒和 目前存在或可能从人畜共患病水库中出现的MerbecoVirus。PPG 将11个领先实验室的工作与具有专业知识的合作记录相结合 在冠状病毒生物学、病毒发病机制、B和T细胞免疫、疫苗开发、动物 挑战研究，结构生物学，抗体结构和功能，抗原设计，以及 病毒的进化分析。所有项目和核心都计划与专注的 目标设计优化的B和T细胞抗原并入腺病毒(CHAD)和 水疱性口炎病毒(VSV)载体创造黏膜和系统疫苗，以保护 预防由一系列可能引起关注的冠状病毒引起的感染和疾病。PPG 由执行疫苗接种和感染的中央动物挑战核心提供服务 小鼠和仓鼠的实验和一个简化数据的中央管理核心 管理和共享，为下一步选择和科学提供计算分析 决策，并促进沟通。我们的建议和抗原设计程序服务于 作为乍得疫苗、VSV疫苗的可能产品开发的蓝图，或 即使使用其他平台(例如，信使核糖核酸疫苗、纳米颗粒等)在这里不直接评估。 根据我们的PPG的结论，我们预计会产生至少一种并且可能是多种病毒- 诱导多种冠状病毒广谱免疫的载体疫苗平台 令人担忧的问题包括可能出现的人类和人畜共患肉瘤病毒和分枝杆菌病毒 未来。

Overall Summary Given the historical outbreaks of coronaviruses, coupled with the recent emergence of SARS- CoV-2 and the destabilizing consequence of COVID-19 on global health and economy, there is an urgent and critical need to develop new vaccines capable of broad protection against existing and future Sarbecoviruses and Merbecoviruses. This P01 program project (PPG) addresses the hypothesis that a combination of evolutionarily-designed and optimized B and T cell antigens can confer broad and protective immunity against Sarbecoviruses and Merbecoviruses that currently exist or could emerge from zoonotic reservoirs. The PPG integrates the work of eleven leading laboratories with records of collaboration that have expertise in coronavirus biology, viral pathogenesis, B and T cell immunity, vaccine development, animal challenge studies, structural biology, antibody structure and function, antigen design, and evolutionary analysis of viruses. All Projects and Cores plan interactive studies with the focused goal of designing optimized B and T cell antigens for incorporation in adenoviral (ChAd) and vesicular stomatitis virus (VSV) vectors to create mucosal and systemic vaccines that protect against infection and disease caused by a range of coronaviruses of potential concern. The PPG is served by a central Animal Challenge Core that performs vaccination and infection experiments in mice and hamsters and a central Administrative Core that streamlines data management and sharing, provides computational analysis for down-selection and scientific decision-making, and facilitates communication. Our proposal and antigen design program serves as a blueprint for possible product development with ChAd vaccines, VSV-based vaccines, or even with other platforms (e.g., mRNA vaccines, nanoparticles, etc.) not directly evaluated here. By the conclusion of our PPG, we envision generating at least one and likely multiple viral- vectored vaccine platforms that induce broad spectrum immunity to multiple coronaviruses of concern including human and zoonotic Sarbecoviruses and Merbecoviruses that could emerge in the future.