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Structure-guided design of a safe and effective Respiratory Syncytial Virus G protein immunogen

安全有效的呼吸道合胞病毒G蛋白免疫原的结构引导设计

基本信息

批准号：
9983875
负责人：
Rebecca Michelle DuBois
金额：
$ 55.86万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9983875
关键词：
Affinity Amino Acids Antibodies Antibody Binding Sites Antibody Response Antigens Antiviral Agents Avidity Binding Blocking Antibodies Body Weight decreased Cells Cellular Infiltration Child Complex Data Development Disabled Persons Elderly Engineering Epithelial Cells Epitopes Essential Amino Acids GTP-Binding Proteins Generations Goals Immune Immune response Immunity Immunization Immunocompromised Host Immunology Individual Infant Innate Immune Response Lower respiratory tract structure Lung Lung diseases Measurement Mediating Molecular Conformation Monoclonal Antibodies Morbidity - disease rate Mus Mutagenesis Pathway interactions Population Positioning Attribute Protein Engineering Proteins Pulmonary Pathology Research Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory Tract Diseases Respiratory syncytial virus Safety Severity of illness Signal Transduction Standardization Structural Protein Structure Surface Testing Toxic effect Vaccinated Vaccination Vaccine Antigen Vaccine Research Vaccines Viral Load result Viral Respiratory Tract Infection Virus Virus Diseases X-Ray Crystallography chemokine receptor cytokine design human monoclonal antibodies immunogenic immunogenicity improved in vivo insight interdisciplinary approach mortality mutant novel pathogenic virus preservation prevent protein structure response three dimensional structure virology

项目摘要

PROJECT SUMMARY Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract disease in young children worldwide, and is also a major cause of morbidity in the elderly and immunocompromised populations. No approved RSV vaccine exists. Our goal is to utilize a structure-guided design approach to rationally engineer RSV G protein immunogens that induce safe and protective immunity against RSV. RSV G protein is one of two major immunogenic proteins on the RSV surface and has key roles in virus attachment to airway epithelial cells and virus modulation of innate immune defenses. RSV G protein is the target of broadly neutralizing, protective antibodies, however its development as a vaccine immunogen has been hampered by safety concerns with its immune-modulating activity on chemokine receptor CX3CR1+ cells and by a paucity of structural information on its epitopes. In this proposal, we will test our central hypothesis that an engineered RSV G immunogen that cannot activate CX3CR1+ cells but does display protective conformational epitopes will elicit safe and effective RSV immunity. We will use an integrated, multidisciplinary approach with experts in RSV G protein structure and engineering (DuBois) and RSV virology and immunology (Tripp) to pursue four specific aims: (1) Use structural studies to define both the conserved RSV G protein epitopes recognized by protective antibodies and the binding site for the chemokine receptor CX3CR1, (2) Use structure-guided design to engineer RSV G protein immunogens, (3) Use a multi-parameter immunology approach to evaluate 3 engineered RSV G protein immunogens for improved safety and immunogenicity, and (4) Evaluate 2-3 engineered RSV G protein immunogens for safety and ability to prevent RSV infection and disease in mice. The proposed research will generate a single engineered RSV G vaccine immunogen with demonstrated safety and efficacy in preventing RSV infection and disease in vivo.

项目总结呼吸道合胞病毒(Rsv)是引起青少年严重下呼吸道疾病的主要原因。该疾病在世界各地的儿童中流行，也是老年人和免疫功能受损人群发病的主要原因。不存在已批准的RSV疫苗。我们的目标是利用结构导向的设计方法来合理地改造RSV G蛋白免疫原，诱导对RSV的安全和保护性免疫。RSV G蛋白是呼吸道合胞病毒表面的两种主要免疫原性蛋白之一，在病毒附着到呼吸道中起关键作用上皮细胞和病毒调节的先天免疫防御。RSV G蛋白是广泛研究的靶点然而，它作为疫苗免疫原的发展受到了以下方面的阻碍关于其对趋化因子受体CX3CR1+细胞的免疫调节活性以及缺乏关于其表位的结构信息。在这个提案中，我们将测试我们的中心假设，即一个工程设计的 RSV G免疫原，不能激活CX3CR1+细胞，但显示保护性构象表位会引起安全有效的呼吸道合胞病毒免疫。我们将与专家一起使用综合的、多学科的方法 RSV G蛋白结构和工程学(DuBois)和RSV病毒学和免疫学(TRIP)追求四个具体目标：(1)利用结构研究确定RSV G蛋白识别的保守表位趋化因子受体CX3CR1的保护性抗体和结合部位，(2)采用结构导向设计设计RSV G蛋白免疫原，(3)使用多参数免疫学方法评估3 改良RSV G蛋白免疫原以提高安全性和免疫原性，以及(4)评估2-3 经过改造的RSV G蛋白免疫原，用于安全和有能力预防RSV感染和小鼠疾病。这项拟议的研究将产生一种单一的工程RSV G疫苗免疫原，并证明体内预防呼吸道合胞病毒感染和疾病的安全性和有效性。