B Cell Epitope Discovery and Mechanisms of Antibody Protection: Responses to Dengue 4, Powassan, Chikungunya, and Venezuelan Equine Encephalitis Viruses

B 细胞表位发现和抗体保护机制：对登革热 4、Powassan、基孔肯雅热和委内瑞拉马脑炎病毒的反应

• 批准号: 10909763
• 负责人: DAVED FREMONT
• 金额: $ 167.17万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-16 至 2024-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10909763
• 关键词: Affinity; Alphavirus; Antibodies; Antibody Response; Antibody-mediated protection; Antigen Targeting; Antigens; B-Lymphocyte Epitopes; Biological Assay; Chikungunya virus; Complex; Computer software; Contractor; Contracts; Cryoelectron Microscopy; Data; Databases; Dengue; Dengue Virus; Development; Epitope Mapping; Epitopes; Escape Mutant; Evaluation; Evolution; Flavivirus; Foundations; Generations; Glycoproteins; Goals; Human; Immune; Immunization; In Vitro; Infection; Investigation; Kinetics; Mass Spectrum Analysis; Methods; Monoclonal Antibodies; Nonstructural Protein; Pathogenesis; Pathologic; Powassan virus; Process; Production; Proteins; Protocols documentation; Recombinant Proteins; Resources; Role; Sampling; Support Contracts; System; Therapeutic; Validation; Venezuelan Equine Encephalitis Virus; Venezuelan Equine Encephalomyelitis; Viral; Virus; West Nile; X-Ray Crystallography; Zika Virus; antigen binding; arthropod-borne; chikungunya; human monoclonal antibodies; in vivo; mouse model; mutation screening; particle; pathogen; pathogenic virus; response; vaccine development; viral transmission

This contract supports the identification of human B cell epitopes derived from four viral pathogens; Dengue virus 4, Powassan virus, Chikungunya virus, and Venezuelan equine encephalitis virus, combined with basic studies to understand protective immunity mediated by antibodies, as well as pathological consequences of antibody responses. Milestones include 1) epitope identification; 2) epitope validation that must include in vitro evaluation using human samples; 3) submission of epitope data, computer software, and structural data to the Immune Epitope Database and Analysis Resource; and 4) studies to help understand the mechanisms of protection or pathogenesis elicited by antibodies associated with the newly identified epitopes. The primary goal of this contract is the delineation of B cell epitopes recognized by potently neutralizing or protective antibodies and evaluation of correlates of protection that can aid in the development of vaccines and therapeutics against select arthropod-transmitted viruses. The Contractor has chosen two flaviviruses (Dengue virus 4 and Powassan virus) and two alphaviruses (Chikungunya virus and Venezuelan equine encephalitis) for primary investigation of antibody responses to viral glycoprotein antigens. The Contractor will also evaluate protective antibodies that recognize the flavivirus nonstructural protein 1 (NS1) produced by West Nile and Zika viruses.

该合同支持鉴定从四个病毒病原体中得出的人类B细胞表位。登革热病毒4，Powassan病毒，基孔肯雅病毒和委内瑞拉马脑炎病毒，结合基础研究，以了解抗体介导的保护性免疫以及抗体反应的病理后果。里程碑包括1）表位识别； 2）表位验证必须包括使用人类样品进行体外评估； 3）向免疫表位数据库和分析资源提交表位数据，计算机软件和结构数据； 4）研究有助于了解与新确定的表位相关的抗体引起的保护或发病机理的机理。该合同的主要目的是通过严格中和或保护性抗体的识别和保护相关性评估B细胞表位的描述，这些抗体可以帮助开发疫苗和治疗剂，以防止针对某些节肢动物传播的病毒毒素。承包商选择了两种黄病毒（登革热病毒4和Powassan病毒）和两种α（Chikungunya病毒和委内瑞拉省马脑炎），用于对病毒糖蛋白抗原的抗体反应的主要研究。承包商还将评估识别西尼罗河和寨卡病毒产生的黄病毒非结构蛋白1（NS1）的保护性抗体。