Consortium for Immunotherapeutics against Emerging Viral Threats

针对新兴病毒威胁的免疫治疗联盟

• 批准号: 10447562
• 负责人: Erica Ollmann Saphire
• 金额: $ 190.37万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-17 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447562
• 关键词: 2019-nCoV; ACE2; Adopted; Animal Model; Antibodies; Antibody Binding Sites; Antibody Response; Antigens; Binding; Binding Proteins; Biological Assay; COVID-19; COVID-19 vaccine; Cellular Assay; Communities; Complex; Coronavirus; Data; Databases; Development; Disease; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Epitopes; Feedback; Fostering; Goals; Human; Immune Targeting; Immune response; Immunization; Immunotherapeutic agent; Individual; Infection; Knock-in; Lead; Length; Link; Measures; Monoclonal Antibodies; Mus; Mutation; Mutation Analysis; Pathogenesis; Peripheral Blood Mononuclear Cell; Plasma; Positioning Attribute; Property; Proteins; Published Comment; Research Personnel; Resistance; Resources; Role; SARS-CoV-2 antibody; SARS-CoV-2 infection; SARS-CoV-2 spike protein; SARS-CoV-2 variant; Sampling; Site; Standardization; Structure; TMPRSS2 gene; Testing; Therapeutic antibodies; Time; Vaccinated; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Virus; base; community building; data dissemination; data sharing; design; in vivo; member; mouse model; multidisciplinary; neonatal Fc receptor; novel; novel vaccines; resistance mutation; response; therapeutic candidate; tool; vaccine access; vaccine development; vaccine efficacy; vaccine-induced antibodies; variants of concern; web-accessible

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.

抽象的 SARS-COV-2迅速出现并在全球范围内传播，以感染数百万的人。 SARS-COV-2 尖峰蛋白是免疫反应的主要目标，因此大多数疫苗开发工作 尖峰蛋白作为免疫原，可引起保护性抗体。但是，随着SARS-COV-2感染激增 在多个波中，出现了峰值蛋白突变的病毒，这使疫苗是 基于峰值蛋白的初始序列开发。这些变体的持久性和 新变体的不可避免的发展需要继续努力开发新型免疫原子 基于SARS-COV-2尖峰，可以在面对新的情况下获得持久的保护 突变。冠状病毒免疫疗法联盟（Covic）已收集数百个单克隆 全球研究人员的抗体，正在进行广泛，深度和多学科分析 这些抗体的结合位点，以了解尖峰上的哪些表位与 保护。我们将在原子水平上检查保护性抗体的结合足迹并评估 某些表位是否对峰值突变的影响更具抗性。我们还将测试一只新型鼠标 SARS-COV-2感染的模型，该模型涉及人ACE2，TMPRSS2和FCRN的三敲蛋白的小鼠。 这些小鼠可以更好地概括保护性抗体的感染机理和药代动力学的机理 响应疫苗接种而引起。我们将使用这些小鼠检查抗体的保护能力 来自目前接种疫苗的人的纵向样本。鉴于数据的关键作用 共享和传播对新兴突变的快速响应并最大程度地利用信息 我们正在建立更广泛的科学界在这项提案中生成的COVIC数据库，称为 COVIC-DB，允许实时传播和分析此阵列的信息 抗体。 Covic-DB是一个开放的，可访问的数据库，将作为长期资源 了解针对SARS-COV-2尖峰蛋白的抗体的关键特性。