Rapid antibody screening systems to identify and engineer antiviral protection

项目总结 对分子和细胞获得性免疫反应的详细了解对于加速 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不适用于大规模临床样本分析，并且可以提供 关于中和抗体在人体免疫中的作用范围的信息有限。重要的是，当前 这些方法也无法改造抗体分子来直接提高中和效力，这是一种 对发现有效和广泛反应的基于抗体的病毒疾病干预措施的主要限制。 目前的方法也不能设计出针对相关病毒的广泛抗体中和，这对 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 贝塔冠状病毒和黄病毒的谱系，其中对进化和扩展的病毒谱系的保护是 对于有效的临床使用是必不可少的。 该项目将为抗体中和工程的快速分析和工程提供一个新的体外平台。 我们将建立高通量直接选择所需抗病毒特性的抗体的方法，包括 中和的广度和效力。我们将应用一个定制平台，用于本地配对抗体重型和 从人类免疫反应中捕获轻链基因以定位抗病毒抗体的中和能力 由自然感染或疫苗接种引起的，并选择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SARS病毒抗体的发现和工程- CoV-2，它在最近进入人类种群后仍在不断进化。该项目将确定 来自新冠肺炎恢复期患者免疫反应的高效性和广泛性抗体变体。 我们还将设计有希望的抗体，以增强中和广度和对抗不同 SARS-CoV-2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 以发热病毒为关键模型系统。黄病毒抗体依赖性增强产生有效抗体 中和是任何基于抗体的临床干预的关键特征.我们会找出有效的中和 来自接种黄热病病毒疫苗的患者的抗体，以及工程师改进的中和抗体 高效抗多种黄热病病毒株 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而快速的抗病毒抗体发现平台，可以加速 开发针对病毒疾病的医学干预措施的进展。

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.