Coronavirus vaccine development

当中东呼吸综合征冠状病毒爆发引起全球健康担忧时，我们启动了开发候选疫苗的计划。基于先前解决HKU1（一种地方性乙型冠状病毒）刺突结构的研究，并找到稳定MERS-CoV和SARS-CoV刺突蛋白的稳定突变，以及先前与业界的研究合作协议，我们能够快速应对SARS-CoV-2的出现。当序列可用时，我们立即订购试剂来生产刺突蛋白，用于结构研究，用于血清学分析的开发，以及用于从幸存者中分离B细胞以发现抗体的探针。我们与Moderna合作，利用之前研究的信息，基于SARS-CoV-2的稳定刺突结构开发了一种mRNA疫苗。为了表征这种疫苗，我们在仓鼠、小鼠和NHPs中进行了体内研究。我们最近的工作重点是评估疫苗接种后的免疫反应，了解病毒变异对免疫的影响，并试图确定保护的相关性。用mRNA-1273免疫仓鼠、小鼠和NHPs证明具有免疫原性，并引起中和性体液反应。我们发现它可以保护小鼠和NHPs的上呼吸道和下呼吸道感染。我们还了解到，mRNA-1273在nps中引发的s特异性抗体水平与SARS-CoV-2攻击后上呼吸道和下呼吸道病毒复制量相关。此外，我们的研究表明，免疫接种次数影响保护作用，两剂mRNA-1273疫苗方案可保护NHPs免受β感染。这项工作验证了我们所倡导的大流行预防的原型病原体方法，作为一种主动的方法，它将系统地建立试剂和知识库，以应对已知感染人类的所有25个病毒家族。为应对一种新的病毒大流行威胁而采取的这一前所未有的应对措施，将成为应对未来新出现病毒的模板。

When the MERS CoV outbreak raised global health concerns, we initiated a program to develop a candidate vaccine. Based on prior studies to solve the spike structure of HKU1 (an endemic betacoronavirus) and finding stabilizing mutations that also stabilized MERS-CoV and SARS-CoV spike proteins, and prior research collaboration agreements with industry, we were able to respond quickly to the emergence SARS-CoV-2. When sequences were available we immediately ordered reagents to produce spike protein for structural studies, for the development of serological assays, and for probes to isolate B cells from survivors for antibody discovery. In collaboration with Moderna, we used information from our prior studies to develop a mRNA vaccine based on the stabilized spike structure of SARS-CoV-2. To characterize this vaccine we conducted in vivo studies in hamsters, mice and NHPs. Our recent work has focused on assessing the immune response following vaccination, understanding the impact of viral variants on immunization and attempting to define a correlate of protection. Immunization of hamsters, mice and NHPs with mRNA-1273 proved to be immunogenic and elicit a neutralizing humoral response. We showed it protects both upper and lower airway infection in mice and NHPs. We have also learned that mRNA-1273 elicited S-specific antibody levels correlated with the amount of viral replication in the upper and lower airway following SARS-CoV-2 challenge in NHPs. Furthermore, our studies have shown that the number of immunizations impacts protection and that a two-dose mRNA-1273 vaccine regimen protects NHPs from beta infection. This work has validated the prototype pathogen approach to pandemic preparedness that we have advocated as a proactive method that would systematically establish the reagents and knowledge base needed to address all 25 virus families known to infect humans. The steps taken to make this unprecedented response to a new viral pandemic threat will serve as a template for responses to future emerging viruses.