Coronavirus vaccine development

当MERS冠状病毒暴发引发全球健康担忧时，我们启动了一项开发候选疫苗的计划。基于先前解决HKU1(一种地方性贝塔冠状病毒)尖峰结构的研究，以及找到稳定MERS-CoV和SARS-CoV尖峰蛋白的稳定突变，以及先前与业界的研究合作协议，我们能够对SARS-CoV-2的出现做出快速反应。当序列可用时，我们立即订购试剂来生产尖峰蛋白，用于结构研究，用于发展血清学分析，并用于从幸存者中分离B细胞以用于抗体发现的探针。在与莫德纳的合作中，我们利用之前研究的信息开发了一种基于SARS-CoV-2稳定尖峰结构的mRNA疫苗。为了确定这种疫苗的特性，我们在仓鼠、小鼠和NHP中进行了活体研究。我们最近的工作集中在评估接种疫苗后的免疫反应，了解病毒变异对免疫的影响，并试图定义保护的相关性。用mRNA-1273免疫仓鼠、小鼠和NHP可产生中和体液反应，具有免疫原性。我们证明了它既能保护小鼠的上呼吸道感染，也能保护下呼吸道感染和NHP。我们还了解到，在非典型肺炎冠状病毒2型攻击后，S特异性抗体水平与上、下呼吸道病毒复制量相关。此外，我们的研究表明，免疫次数影响保护，两剂mRNA-1273疫苗方案保护NHP免受贝塔感染。这项工作验证了我们所倡导的预防大流行的病原体原型方法，它是一种积极主动的方法，将系统地建立解决所有25个已知感染人类的病毒家族所需的试剂和知识库。为应对新的病毒大流行威胁而采取的这一史无前例的措施将成为应对未来新出现的病毒的模板。

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.