Rapid antibody screening systems to identify and engineer antiviral protection

项目概要 详细了解分子和细胞适应性免疫反应对于加速免疫反应至关重要 人类免疫学和药物开发的进展。然而，用于分析抗病毒药物的现有技术 中和抗体反应缓慢且对于大规模临床样本分析来说不切实际，并且可以提供 关于人类免疫中中和抗体特征范围的信息有限。重要的是，当前 方法也无法设计抗体分子来直接提高中和效力，这是一个 发现针对病毒性疾病的有效且具有广泛反应性的基于抗体的干预措施的主要限制。 目前的方法也无法设计针对相关病毒的广泛抗体中和，这对于 针对不同病毒谱系的药物和疫苗开发。重要的例子包括多样化的病毒 β冠状病毒和黄病毒谱系，其中针对进化和扩展的病毒谱系的保护是 对于有效的临床使用至关重要。 该项目将开发一个新的体外平台，用于抗体中和的快速分析和工程设计。 我们将建立以高通量直接选择所需抗病毒特性的抗体的方法，包括 中和广度和效力。我们将为天然配对的抗体重和抗体应用定制平台 从人类免疫反应中捕获轻链基因以绘制抗病毒抗体的中和能力 由自然感染或疫苗接种引起，并选择针对相关病毒的广泛抗体保护。 目标 1 将建立我们的新检测技术，用于抗病毒抗体的发现和工程设计，以对抗 SARS- CoV-2，最近出现在人类群体中后正在不断进化。该项目将确定 来自恢复期 COVID-19 患者免疫反应的高效力和广度的抗体变体。 我们还将设计有前景的抗体，以增强针对多种病毒的中和广度和效力。 SARS-CoV-2 毒株。 目标 2 将建立针对黄病毒的抗病毒抗体发现和工程策略，使用黄色 发热病毒作为关键模型系统。黄病毒中的抗体依赖性增强产生了有效的抗体 中和作用是任何基于抗体的临床干预措施的关键特征。我们将确定有效的中和剂 来自接种黄热病病毒疫苗的患者的抗体，并设计改进的中和抗体 对多种黄热病病毒株具有高效力 这项工作将为有效的抗病毒发现和抗体工程建立一个新的平台方法。我们的 长期目标是开发强大且快速的抗病毒抗体发现平台，以加速 病毒性疾病医疗干预措施的发展取得进展。

PROJECT SUMMARY A detailed understanding of molecular and cellular adaptive immune responses is critical to accelerate progress in human immunology and drug development. However, available technologies for analyzing antiviral neutralizing antibody responses are slow and impractical for large-scale clinical sample analysis, and can provide limited information on the scope of neutralizing antibody features in human immunity. Importantly, current methods are also unable to engineer antibody molecules to directly improve neutralization potency, which is a major limitation to the discovery of potent and broadly reactive antibody-based interventions for viral diseases. Current methods also cannot engineer broad antibody neutralization against related viruses, which is critical for drug and vaccine development against diverse viral lineages. Important examples include the diverse viral lineages of betacoronaviruses and flaviviruses, where protection against evolved and expanded viral lineages is essential for effective clinical use. This project will develop a new in vitro platform for rapid analysis and engineering of antibody neutralization. We will establish methods to directly select antibodies desired antiviral properties at high throughput, including for neutralization breadth and potency. We will apply a custom platform for natively paired antibody heavy and light chain gene capture from human immune responses to map the neutralization capacity of antiviral antibodies elicited by natural infection or vaccination, and to select for broad antibody protection against related viruses. Aim 1 will establish our new assay techniques for antiviral antibody discovery and engineering against SARS- CoV-2, which is continuously evolving after its recent emergence into human populations. This project will identify antibody variants with high potency and breadth from the immune responses of convalescent COVID-19 patients. We will also engineer promising antibodies for enhanced neutralization breadth and potency against diverse SARS-CoV-2 strains. Aim 2 will establish antiviral antibody discovery and engineering strategies against flaviviruses, using yellow fever virus as a key model system. Antibody-dependent enhancement in flaviviruses makes potent antibody neutralization a critical feature for any antibody-based clinical interventions. We will identify potent neutralizing antibodies from patients vaccinated against yellow fever virus, and engineer improved neutralizing antibodies for high potency against multiple yellow fever virus strains This work will establish a new platform approach for potent antiviral discovery and antibody engineering. Our long-term objectives are to develop robust and rapid antiviral antibody discovery platforms that can accelerate progress in the development of medical interventions for viral diseases.