Structural Characterization of Coronavirus Antibodies Raised by Infection and Vaccination

感染和疫苗接种产生的冠状病毒抗体的结构表征

• 批准号: 10841242
• 负责人: Pamela J Bjorkman
• 金额: $ 97.15万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-03 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10841242
• 关键词: 2019-nCoV; Abbreviations; Animal Experiments; Animal Model; Animals; Antibodies; Antibody Response; Binding; Biochemical; Biological Assay; COVID-19; COVID-19 vaccination; Chiroptera; Collaborations; Common Cold; Complement; Complementarity Determining Regions; Complex; Coronavirus; Coronavirus spike protein; Cryoelectron Microscopy; Disease; Disease Outbreaks; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Evaluation; Future; Human; Immunization; Immunize; Immunoglobulin Somatic Hypermutation; Infection; Laboratories; Light; Merbecovirus; Molecular Sieve Chromatography; Monoclonal Antibodies; Mus; Negative Staining; Persons; Plasma; Publications; Resolution; Rice; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 infection; Sarbecovirus; Severe Acute Respiratory Syndrome; Structure; Surface Plasmon Resonance; Testing; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Virus; Zoonoses; betacoronavirus; convalescent plasma; cross reactivity; experimental study; follow-up; improved; mosaic; mutant; nanoparticle; neutralizing antibody; pandemic coronavirus; pandemic disease; pandemic potential; particle; receptor binding; response; serosurveillance; structural biology; three dimensional structure; transmission process; universal coronavirus vaccine; vaccine candidate; zoonotic coronavirus

Project 3: Summary/Abstract SARS-CoV-2, a newly-emergent betacoronavirus in the sarbecovirus genus, resulted in a global pandemic in 2020, infecting millions and causing COVID-19 disease. Two other zoonotic betacoronaviruses, SARS-CoV (a sarbecovirus) and MERS-CoV (a merbecovirus), also resulted in outbreaks within the last 20 years. SARS-like viruses circulate in bats and serological surveillance of people living near caves where bats carry diverse coronaviruses demonstrate direct transmission of SARS-like viruses with pandemic potential, suggesting a pan- coronavirus vaccine is needed. In Project 3, the Bjorkman lab will use structural biology and biochemical approaches to understand the neutralization mechanisms of antibodies (Abs) elicited in humans by SARS-CoV- 2 infection or vaccination and in experimental animals by immunization. In Aim 1, using 3D structures of Ab Fabs bound to coronavirus spike (S) trimers, we will derive the structural correlates of neutralization/binding for monoclonal Abs (mAbs) and polyclonal plasmas isolated in Project 1 by Dr. Nussenzweig from (i) humans infected by SARS-CoV-2 after ~1 month, (ii) matured human Abs isolated ½ - 2 years after infection, (iii) humans vaccinated against SARS-CoV-2 with the Moderna vaccine, and (iv) animals immunized with vaccine candidates developed in Project 2 by Drs. Bieniasz and Hatziioannou or developed in this project's Aim 2 in the Bjorkman laboratory. Aim 2 of this project will follow up on our lab's evaluations of the potential for cross-reactive antibody responses to sarbecoviruses, for which we made homotypic nanoparticles presenting the receptor-binding domain (RBD) of only SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses (mosaic nanoparticles; 4-8 distinct RBDs). By combining results of functional analyses of Ab neutralization derived from pseudotyped and authentic virus neutralization assays in collaboration with Dr. Rice with structural analyses of Abs isolated from RBD-nanoparticle–injected mice, we will refine our nanoparticle vaccine candidate(s) to increase their potential to protect against sarbecoviruses. Furthermore, we will develop additional vaccine candidates against merbecoviruses and/or alphacoronaviruses that will be evaluated along with the best pan-sarbecovirus vaccine in animal models of protection by Dr. Rice and/or our NIH collaborator, Dr. Vincent Munster. This highly-integrated project has the potential to contribute to creation of vaccine(s) that could avert future global pandemics.

项目3：摘要/摘要 SARS-CoV-2是一种新出现的β冠状病毒，在2004年导致全球大流行。 2020年，感染数百万人并导致COVID-19疾病。其他两种人畜共患β冠状病毒，SARS-CoV（a Sarbecovirus）和MERS-CoV（一种merbecovirus）也在过去20年内导致了疫情。sars样 病毒在蝙蝠中传播，对居住在蝙蝠携带多种病毒的洞穴附近的人进行血清学监测， 冠状病毒证明了SARS样病毒的直接传播，具有大流行的潜力，这表明一个泛- 需要冠状病毒疫苗。在项目3中，Bjorkman实验室将使用结构生物学和生物化学 了解SARS-CoV在人体内引发的抗体（Abs）中和机制的方法- 2感染或接种，并在实验动物中通过免疫接种。在目的1中，使用Ab Fab的3D结构， 结合冠状病毒刺突（S）三聚体，我们将推导出中和/结合的结构相关性， Nussenzweig博士在项目1中从（i）人类分离的单克隆抗体（mAb）和多克隆血浆 感染SARS-CoV-2约1个月后，（ii）感染后1/2 - 2年分离的成熟人Ab，（iii）人 用Moderna疫苗接种SARS-CoV-2疫苗，以及（iv）用候选疫苗免疫的动物 由Bieniasz和Hatzioannou博士在项目2中开发，或在Bjorkman的项目目标2中开发 实验室本项目的目标2将跟踪我们实验室对交叉反应抗体的可能性的评估 对肉瘤病毒的反应，为此我们制作了呈现受体结合的同型纳米颗粒 仅SARS-CoV-2的结构域（RBD）或与来自动物的RBD一起共展示SARS-CoV-2 RBD沿着 β冠状病毒（镶嵌纳米颗粒; 4-8个不同的RBD）。结合抗体功能分析结果， 与Rice博士合作，从假型和真实病毒中和试验中获得中和作用 通过对从注射RBD纳米颗粒的小鼠中分离的抗体的结构分析，我们将改进我们的纳米颗粒， 候选疫苗，以增加其预防肉瘤病毒的潜力。此外，我们将开发 将沿着进行评价的其他针对merbecoviruses和/或Escheracoronaviruses的候选疫苗 在Rice博士和/或我们的NIH合作者的动物保护模型中使用最好的泛肉瘤病毒疫苗， 博士文森特·蒙斯特。这个高度整合的项目有可能有助于创造疫苗， 可以避免未来的全球流行病。