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: 10390727
• 负责人: James J Kobie
• 金额: $ 85.64万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390727
• 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; Immunoglobulin Variable Region; Immunoglobulins; Immunologics; Incidence; Individual; Infection; Inhalation; K-18 conjugate; Maintenance; Mediating; Mesocricetus auratus; Monoclonal Antibodies; Ontology; Patients; Phase I/II Clinical Trial; Phenotype; Plasma; Population; Predisposition; Proteins; Recombinants; Reporting; Resolution; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Serology; Structure; System; Testing; Therapeutic; Transgenic Mice; Vaccinated; Vaccination; Vaccines; Variant; Viral; Virus; Work; base; cohort; design; drug efficacy; expectation; in vitro activity; in vivo; mouse model; neutralizing antibody; next generation; pandemic disease; preservation; pressure; prospective; receptor binding; response; scaffold; transmission process; 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.

项目摘要 SARS-COV-2感染了超过1.38亿的人，到目前为止，死亡人数超过280万，其中 期望大流行将持续数月，并且该病毒将在数年中持续存在， 受关注的新兴变体（VOC）加剧。尽管几种疫苗被广泛使用，但 尚不清楚他们是否能够诱导有效的长期免疫力，以防止新兴的VOC。高效抗 SARS-COV-2的病毒疗法仍然难以捉摸，尽管几种靶向的单克隆抗体（mAb） 峰值蛋白的受体结合结构域（RBD）已被授予EUA，以用于轻度至中度感染， 它们针对严重疾病的有效性尚不明显。随着全球疫苗接种速度缓慢， 有限的抗病毒使用/功效，以及抗原漂移变体的出现，这种大流行的轨迹和 该病毒的未来复兴引起了人们的关注。对诱导机制的基本理解 维持对SARS-COV-2的保护性体液免疫对于缓解至关重要。现在病毒 分为几个进化枝，无数的voc新兴以及包括我们的作品在内的迹象和其他一些 这种抗原漂移的结果是病毒因免疫压力而逃脱并增加的可传播性。漂移 在RBD中是最大的关注，因为它可以增强病毒的感染力并消除活性 可能是从先前的疫苗接种或感染中发展出来的NAB。已经出现了许多报告 患者的重复SARS-COV-2感染以及完全疫苗接种的个体突破性感染， 强调自然获得的SARS-COV-2免疫的不完美。利用我们的理性设计 RBD/RBD-ACE2融合蛋白变体，我们已经确定了表型异质性 RBD特异性的人B细胞，并分离了几个有效的RBD特异性人类中和单克隆ABS （NMAB）（IC50 <50 ng/ml）针对SARS-COV-2，该SARS-COV-2使用吸入阶段进行1/2临床试验 在接下来的几个月中交付。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的期望的表位被可变区域所包围（RBD- VR）在结构上动态且高度容易受到抗原漂移的影响。此外，我们假设RBD-VR 通过他们的来减轻有效和广泛的RBD-CR特定体液反应的发展 RBD-CR的免疫效力和直接阻塞。这种RBD-CR/RBD-VR进化动态可能可能是 调节对未来病毒变异的体液反应的持续保护（或失败）。我们将1）定义 人RBD特异性抗体反应的本体论和表型多样性，2）定义 维持ACE2结合和免疫压力对约束RBD演变的动力学，3） 确定对SARS-COV-2漂移的RBD AB公差和贡献。定义自然感染的极限和 疫苗接种引起的RBD中和抗体，以驱动抗原漂移并赋予防止发散的抗体 SARS-COV-2病毒将为下一代SARS-COV-2疫苗和治疗剂提供信息。