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.

该合同支持鉴定源自四种病毒病原体的人类 B 细胞表位；登革热病毒4型、波瓦桑病毒、基孔肯雅病毒和委内瑞拉马脑炎病毒，结合基础研究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) 表位鉴定； 2) 表位验证，必须包括使用人体样本进行体外评估； 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）帮助了解与新鉴定的表位相关的抗体引起的保护机制或发病机制的研究。该合同的主要目标是描绘由强效中和或保护性抗体识别的 B 细胞表位，并评估保护相关性，以帮助开发针对特定节肢动物传播病毒的疫苗和治疗方法。承包商选择了两种黄病毒（登革热病毒 4 和波瓦桑病毒）和两种甲病毒（基孔肯雅病毒和委内瑞拉马脑炎）来初步研究抗体对病毒糖蛋白抗原的反应。承包商还将评估识别西尼罗河病毒和寨卡病毒产生的黄病毒非结构蛋白 1 (NS1) 的保护性抗体。