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SARBECOVIRUS属的新发射的Betacoronavirus，导致全球大流行 2020年，感染了数百万美元，并引起了Covid-19疾病。另外两个人畜共动性Betacoronaviruses，SARS-COV（a SARBECOVIRUS）和MERS-COV（Merbecovirus）也导致了过去20年的爆发。类似于萨尔 病毒在蝙蝠和居住在蝙蝠附近的人的血清学监测中圈出蝙蝠带有多种多样的 冠状病毒表现出具有大流行潜力的SARS样病毒的直接传播，表明 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化 了解人类在人类中通过SARS-COV引起的抗体（ABS）神经化机制的方法 2通过免疫感染或疫苗接种以及实验动物。在AIM 1中，使用AB Fabs的3D结构 与冠状病毒尖峰结合，我们将得出神经化/结合的结构相关性 nussenzweig博士在项目1中分离的单克隆ABS（mAb）和多克隆等离子体（i）人类 大约1个月后，由SARS-COV-2感染，（ii）感染后的成熟人类ABS分离½-2年，（iii）人类 用现代疫苗接种SARS-COV-2，并用候选疫苗免疫的（IV）动物 DRS在项目2中开发。 Bieniasz和Hatziioannou或在Bjorkman的该项目的目标2中开发 实验室。该项目的目标2将跟进我们实验室对交叉反应抗体潜力的评估 对SARBECOVIRASE的反应，为此，我们制作了同型纳米颗粒，呈现接收器结合 仅SARS-COV-2或共同播放的SARS-COV-2 RBD的域（RBD）以及动物的RBD Betacoronaviruses（镶嵌纳米颗粒； 4-8个不同的RBD）。通过结合AB功能分析的结果 与赖斯博士合作，源自伪型和正宗病毒神经化测定法的谈判 通过对从RBD纳米颗粒注射的小鼠分离的ABS的结构分析，我们将精炼纳米颗粒 疫苗候选者为了防止SARBecoviruses提高其潜力。此外，我们将发展 针对Merbecoviruses和/或Alphacoronaviruse的其他疫苗候选者将进行评估 用赖斯博士和/或我们的NIH合作者的保护动物模型中最好的PAN-SARBECOVIRUS疫苗在保护动物模型中 文森特·芒斯特博士。这个高度整合的项目有可能为创建疫苗的创造做出贡献 可以避免未来的全球大流行。