The origin and future protective activity of SARS-CoV-2 RBD specific neutralizing antibodies

SARS-CoV-2 RBD 特异性中和抗体的起源和未来保护活性

• 批准号: 10490907
• 负责人: James J Kobie
• 金额: $ 84.12万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490907
• 关键词: 2019-nCoV; ACE2; Address; Affinity; Alleles; Antibody Response; Antigens; Antiviral Agents; B-Lymphocytes; Binding; COVID-19; COVID-19 therapeutics; COVID-19 vaccine; Cessation of life; Chimeric Proteins; Complex; Development; Disease; Effectiveness; Epitopes; Evolution; Failure; Future; Grant; Heterogeneity; Human; Humoral Immunities; Immune; Immunity; Immunoglobulins; Immunologics; Incidence; Infection; Inhalation; K-18 conjugate; Maintenance; Mediating; Mesocricetus auratus; Monoclonal Antibodies; Ontology; Patients; Persons; Phase I/II Clinical Trial; Phenotype; Plasma; Population; Predisposition; Proteins; Recombinants; Reporting; Resolution; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 transmission; SARS-CoV-2 variant; Sampling; Serology; System; Testing; Therapeutic; Transgenic Mice; Vaccination; Vaccinee; Vaccines; Variant; Viral; Virus; Work; base; breakthrough infection; cohort; drug efficacy; expectation; in vitro activity; in vivo; mouse model; neutralizing antibody; next generation; pandemic disease; preservation; pressure; prospective; rational design; receptor binding; response; scaffold; variants of concern

PROJECT SUMMARY SARS-CoV-2 has infected over 138 million people and resulted in over 2.8 million deaths so far, with the expectation the pandemic will continue for many more months, and the virus will persist endemically for years, exacerbated by emerging variants of concern (VoC). Although several vaccines are being used wide-spread, it is unclear if they will be able to induce effective long-term immunity against emerging VoC. Highly effective anti- viral therapeutics for SARS-CoV-2 remain elusive, although several monoclonal antibodies (mAbs) targeting the Receptor Binding Domain (RBD) of the Spike (S) protein have been granted EUA for mild to moderate infection, their effectiveness against severe disease has not yet been evident. With the slow pace of global vaccination, limited anti-viral use/efficacy, and the emergence of antigenic drift variants, the trajectory of this pandemic and future resurgences of the virus is of great concern. Fundamental understanding of the mechanisms of inducing and sustaining protective humoral immunity to SARS-CoV-2 will be critical to its mitigation. The virus is now classified into several clades, numerous VoC emerging, and indications including our work and others that some of this antigenic drift is the result of the virus escaping from immune pressure and increased transmissibility. Drift within the RBD is of the utmost concern as it can enhance the infectivity of the virus and negate the activity of NAbs that may have developed from previous vaccination or infection. Numerous reports have emerged of repeated SARS-CoV-2 infections in patients, and breakthrough infections in fully vaccinated individuals, highlighting the imperfection of naturally acquired SARS-CoV-2 immunity. Utilizing our rationally designed RBD/RBD-ACE2 fusion protein variants, we have identified epitopic and phenotypic heterogeneity amongst RBD-specific human B cells and have isolated several potent RBD-specific human neutralizing monoclonal Abs (NmAbs) (IC50<50 ng/ml) against SARS-CoV-2 which are entering into a Phase 1/2 clinical trial using inhaled delivery in the coming months. We hypothesize that within RBD, the highly conserved regions (RBD-CR), epitopes desirable for mediating broad and potent humoral protection, are surrounded by variable regions (RBD- VR) that are structurally dynamic and highly susceptible to antigenic drift. Further, we hypothesize that RBD-VR mitigate the development of potent and broad RBD-CR specific humoral responses through their immunodominance and direct occlusion of RBD-CR. This RBD-CR/RBD-VR evolutionary dynamic is likely to regulate the sustained protection (or failure) of humoral responses against future viral variants. We will 1) define the ontological and phenotypic diversity of the human RBD-specific neutralizing antibody response, 2) define the dynamics of maintenance of ACE2 binding and immunological pressure on constraining RBD evolution, and 3) determine RBD Ab tolerance for and contribution to SARS-CoV-2 drift. Defining the limits of natural infection and vaccination induced RBD neutralizing antibodies to drive antigenic drift and confer protection from divergent SARS-CoV-2 viruses will inform the development next generation SARS-CoV-2 vaccines and therapeutics.

项目概要 迄今为止，SARS-CoV-2 已感染超过 1.38 亿人，并导致超过 280 万人死亡。 预计大流行将持续数月，病毒将持续流行数年， 新兴的关注变体（VoC）加剧了这种情况。尽管多种疫苗正在广泛使用，但 目前还不清楚它们是否能够对新兴VOC产生有效的长期免疫力。高效抗 尽管有几种针对 SARS-CoV-2 的单克隆抗体 (mAb)，但针对 SARS-CoV-2 的病毒疗法仍然难以捉摸。 Spike (S) 蛋白的受体结合域 (RBD) 已获得 EUA 用于轻度至中度感染， 它们对抗严重疾病的有效性尚未明显。随着全球疫苗接种步伐缓慢， 抗病毒药物的使用/功效有限，以及抗原漂移变异体的出现，这种大流行的轨迹和 病毒未来的卷土重来令人极为担忧。对诱导机制的基本了解 维持针对 SARS-CoV-2 的保护性体液免疫对于缓解其症状至关重要。现在病毒已 分类为几个分支，出现了许多 VOC，并且包括我们的工作和其他一些迹象表明， 这种抗原漂移是病毒逃避免疫压力和传播性增加的结果。漂移 RBD 内的病毒最受关注，因为它可以增强病毒的传染性并消除病毒的活性 可能是因之前的疫苗接种或感染而产生的中性抗体。已经有很多报道出现 患者中反复感染 SARS-CoV-2，以及在完全接种疫苗的个体中出现突破性感染， 突显了自然获得的 SARS-CoV-2 免疫力的缺陷。利用我们合理设计的 RBD/RBD-ACE2 融合蛋白变体，我们已经确定了其中的表位和表型异质性 RBD 特异性人类 B 细胞，并分离出几种有效的 RBD 特异性人类中和单克隆抗体 (NmAbs) (IC50<50 ng/ml) 针对 SARS-CoV-2，正在进入使用吸入的 1/2 期临床试验 未来几个月内交付。我们假设在 RBD 中，高度保守的区域（RBD-CR）， 介导广泛而有效的体液保护所需的表位被可变区（RBD- VR）的结构是动态的，并且非常容易受到抗原漂移的影响。此外，我们假设 RBD-VR 通过它们的作用来减轻有效和广泛的 RBD-CR 特异性体液反应的发展 免疫优势和 RBD-CR 的直接闭塞。这种 RBD-CR/RBD-VR 进化动态很可能 调节针对未来病毒变种的体液反应的持续保护（或失败）。我们将 1) 定义 人类 RBD 特异性中和抗体反应的本体和表型多样性，2) 定义 维持 ACE2 结合的动态和限制 RBD 进化的免疫压力，以及 3) 确定 RBD Ab 对 SARS-CoV-2 漂移的耐受性和贡献。定义自然感染的限度和 疫苗接种诱导 RBD 中和抗体，以驱动抗原漂移并提供针对不同抗原的保护 SARS-CoV-2 病毒将为下一代 SARS-CoV-2 疫苗和治疗方法的开发提供信息。

项目成果

Modeling SARS-CoV-2 and influenza infections and antiviral treatments in human lung epithelial tissue equivalents.

在人肺上皮组织等效物中模拟 SARS-CoV-2 和流感感染以及抗病毒治疗。

• 发表时间: 2022-08-12
• 影响因子: 5.9
• 作者: Zarkoob, Hoda;Allué;Chen, Yu;Garcia;Jung, Olive;Coon, Steven;Song, Min Jae;Park, Jun;Oladunni, Fatai;Miller, Jesse;Tung, Yen;Kosik, Ivan;Schultz, David;Iben, James;Li, Tianwei;Fu, Jiaqi;Porter, F
• 通讯作者: Porter, F

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation.

干扰素 α 诱导蛋白 6 通过调节 RIG-I 激活来负调节先天免疫反应。

• 发表时间: 2023
• 作者: Villamayor, Laura;Rivero, Vanessa;López;Topham, David J;Martínez;Nogales, Aitor;DeDiego, Marta L
• 通讯作者: DeDiego, Marta L

Animal Models of COVID-19: Transgenic Mouse Model.

COVID-19 动物模型：转基因小鼠模型。

• 发表时间: 2022
• 作者: Park, Jun;Pino, Paula A;Akhter, Anwari;Alvarez, Xavier;Torrelles, Jordi B;Martinez
• 通讯作者: Martinez

Selection, identification, and characterization of SARS-CoV-2 monoclonal antibody resistant mutants.

SARS-CoV-2 单克隆抗体抗性突变体的选择、鉴定和表征。

• 发表时间: 2021-04
• 影响因子: 3.1
• 作者: Oladunni, Fatai S;Park, Jun;Chiem, Kevin;Ye, Chengjin;Pipenbrink, Michael;Walter, Mark R;Kobie, James;Martinez
• 通讯作者: Martinez

Mitigation of SARS-CoV-2 by Using Transition Metal Nanozeolites and Quaternary Ammonium Compounds as Antiviral Agents in Suspensions and Soft Fabric Materials.

使用过渡金属纳米沸石和季铵化合物作为悬浮液和软织物材料中的抗病毒剂来缓解 SARS-CoV-2。

• 发表时间: 2023
• 作者: Guerrero;Khan, Siddiqur Rahman;Henry, Brandon M;Garcia;Chiem, Kevin;Ye, Chengjin;Shrestha, Sweta;Knight, Deborah;Cristner, Mark;Hill, Shauna;Waldman, W James;Dutta, Prabir K;Torrelles, Jordi B;Martinez
• 通讯作者: Martinez