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.

摘要 SARS-CoV-2病毒迅速出现并在全球蔓延，感染了数百万人。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都使用 将S蛋白作为免疫原，以诱导保护性抗体。然而，随着SARS-CoV-2感染激增 在多次浪潮中，携带Spike蛋白突变的病毒出现，这使得疫苗成为 基于初始序列开发的尖峰蛋白效果较差。这些变种的持久性和 新变种的可能不可避免的发展需要继续努力开发新的免疫原 基于SARS-CoV-2尖峰病毒，可以引发持久的保护，在面对新的 突变。冠状病毒免疫治疗联盟(COVIC)收集了数百株单抗 来自世界各地研究人员的抗体，正在进行广泛、深入和多学科的分析 这些抗体的结合部位，以了解棘突上的哪些表位与 保护。我们将在原子水平上检查保护性抗体的结合足迹并评估 某些表位是否对尖峰突变的影响更具抵抗力。我们还将测试一种新的鼠标 SARS-CoV-2感染模型，涉及具有人ACE2、TMPRSS2和FcRN三重敲击的小鼠。 这些小鼠可以更好地概括保护性抗体的感染机制和药代动力学。 在接种疫苗后引起的。我们将使用这些小鼠来检验抗体对人的保护能力 来自接受当前可用疫苗的个人的纵向样本。鉴于数据的关键作用 共享和传播，以便对新出现的突变做出快速反应，并最大限度地利用信息 在这项由更广泛的科学界提出的建议中，我们正在建立Covic数据库，称为 Covic-DB，它允许实时传播和分析有关此保护阵列的信息 抗体。COVIC-DB是一个开放的、可通过Web访问的数据库，它将作为长期资源 了解抗SARS-CoV-2刺突蛋白抗体的关键特性。