Consortium for Immunotherapeutics against Emerging Viral Threats

摘要 SARS-CoV-2迅速出现并传播到地球仪，感染了数百万人。SARS-CoV-2 刺突蛋白是免疫应答的主要靶标，因此大多数疫苗开发工作都使用刺突蛋白。 刺突蛋白作为免疫原来引发保护性抗体。然而，随着SARS-CoV-2感染的激增， 在多次浪潮中，出现了刺突蛋白突变的病毒，这使得疫苗 基于刺突蛋白的初始序列开发的效果较差。这些变体的持续存在， 新变异的出现可能是不可避免的，这就要求继续努力开发新的免疫原 基于SARS-CoV-2峰值，可以引起持久的保护，在面对新的 突变。冠状病毒免疫治疗联盟（CoVIC）已经收集了数百个单克隆抗体， 来自世界各地的研究人员的抗体，并正在进行广泛，深入和多学科的分析 这些抗体的结合位点，以了解刺突上的哪些表位与 保护我们将在原子水平上检查保护性抗体的结合足迹， 某些表位是否更能抵抗刺突突变的影响。我们还将测试一种新的老鼠 SARS-CoV-2感染模型，涉及具有人ACE 2、TMPRSS 2和FcRN三重敲入的小鼠。 这些小鼠可以更好地概括感染机制和保护性抗体的药代动力学 是疫苗接种引起的。我们将使用这些小鼠来检查抗体在小鼠中的保护能力。 从接受目前可用疫苗的个人中提取纵向样本。鉴于数据的关键作用 共享和传播，以便对新出现的突变作出快速反应，并最大限度地利用信息 在更广泛的科学界提出的这一建议中，我们正在建立CoVIC数据库， CoVIC-DB，它允许实时传播和分析关于这一系列保护性措施的信息。 抗体的CoVIC-DB是一个开放的、可通过网络访问的数据库，将作为一个长期资源， 了解SARS-CoV-2刺突蛋白抗体的关键特性。

Abstract SARS-CoV-2 rapidly emerged and spread throughout the globe to infect millions of people. The SARS-CoV-2 spike protein is the primary target of the immune response and thus most vaccine development efforts used the spike protein as an immunogen to elicit protective antibodies. However, as SARS-CoV-2 infections surged in multiple waves, viruses bearing mutations in spike protein emerged, which rendered vaccines that were developed based on initial sequences of the spike protein less effective. The persistence of these variants and the likely inevitable development of new variants requires continued efforts to develop novel immunogens based on SARS-CoV-2 spike that can elicit durable protection that remains effective in the face of new mutations. The Coronavirus Immunotherapeutics Consortium (CoVIC) has gathered hundreds of monoclonal antibodies from researchers around the world and is undertaking a broad, deep and multidisciplinary analysis of the binding sites of these antibodies to understand which epitopes on spike are associated with protection. We will examine at an atomic level the binding footprint of protective antibodies and assess whether certain epitopes are more resistant to the effects of spike mutations. We will also test a novel mouse model of SARS-CoV-2 infection that involves mice with triple knockin of human ACE2, TMPRSS2, and FcRN. These mice may better recapitulate the mechanism of infection and pharmacokinetics of protective antibodies elicited in response to vaccination. We will use these mice to examine the protective capacity of antibodies in longitudinal samples from individuals who received currently available vaccines. Given the critical role of data sharing and dissemination for rapid responses to emerging mutations and to maximize use of the information generated in this proposal by the broader scientific community, we are building the CoVIC database, termed CoVIC-DB, which allows real-time dissemination and analysis of information on this array of protective antibodies. CoVIC-DB is an open, web-accessible database that will serve as a long-term resource to understand key properties of antibodies against SARS-CoV-2 spike protein.