Structure-guided engineering to increase respiratory syncytial virus G protein immunogenicity

结构引导工程提高呼吸道合胞病毒G蛋白免疫原性

• 批准号: 10521837
• 负责人: Rebecca Michelle DuBois
• 金额: $ 76.78万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-19 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521837
• 关键词: Affect; Affinity; Antibodies; Antibody Response; Antigens; Binding; Body Weight decreased; CX3CL1 gene; Cells; Cellular Infiltration; Child; Disease; Elderly; Electron Microscopy; Engineering; Epithelial Cells; Epitopes; Essential Amino Acids; Evaluation; Funding; GTP-Binding Proteins; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunocompromised Host; Immunology; Inbred BALB C Mice; Infant; Leukocytes; Lower respiratory tract structure; Lung; Measurement; Molecular Conformation; Morbidity - disease rate; Mus; Mutation; Negative Staining; Pathogenesis; Pathway interactions; Phenotype; Positioning Attribute; Protein Engineering; Proteins; Pulmonary Pathology; Research; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Tract Diseases; Respiratory syncytial virus; Safety; Serum; Severity of illness; Structure; Surface; Testing; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Research; Vaccines; Viral Load result; Viral Pathogenesis; Viral Respiratory Tract Infection; Virus; Virus Diseases; X-Ray Crystallography; airway epithelium; cytokine; design; functional status; glycosylation; human monoclonal antibodies; immunogenic; immunogenicity; improved; insight; interdisciplinary approach; mortality; mutant; novel; pathogenic virus; preservation; prevent; protein complex; protein structure; rational design; response; three dimensional structure; virology

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 and some mortality in the elderly and immunocompromised. No approved RSV vaccine exists. Our goal is to utilize a structure-guided design approach to rationally engineer RSV G protein immunogens that induce robust 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 neutralizing and protective antibodies. The G protein as a vaccine immunogen has been hampered by poor immunogenicity and by a paucity of structural information on its epitopes. In this proposal, we will test our central hypothesis that engineered multimeric RSV G immunogens that display protective conformational epitopes will elicit robust and protective RSV immunity. We will use an integrated approach to pursue four specific aims: (1) Use structural studies to define conserved RSV G protein epitopes recognized by protective antibodies, (2) Use structure-guided design to engineer multimeric RSV G protein immunogens, (3) Evaluate engineered RSV G protein immunogens for improved immunogenicity, and (4) Use a comprehensive immune analysis to evaluate RSV G protein CCD immunogens for balanced cytokine responses and protective antibodies made in response to vaccination. The proposed research will generate RSV G vaccine immunogens as candidates with demonstrated efficacy in preventing RSV infection and disease pathogenesis.

项目概要 呼吸道合胞病毒（RSV）是年轻人严重下呼吸道疾病的主要原因 全世界的儿童，也是老年人和老年人发病和部分死亡的主要原因 免疫功能低下。尚无经批准的 RSV 疫苗。我们的目标是利用结构引导设计 合理设计 RSV G 蛋白免疫原的方法，诱导强大的保护性免疫 RSV。 RSV G 蛋白是 RSV 表面的两种主要免疫原性蛋白之一，在病毒中发挥着关键作用 附着于气道上皮细胞和病毒调节先天免疫防御。 RSV G 蛋白是 中和和保护性抗体的靶标。 G蛋白作为疫苗免疫原受到了阻碍 免疫原性差且缺乏其表位的结构信息。在这个提案中，我们将测试我们的 中心假设是设计出具有保护性构象的多聚体 RSV G 免疫原 表位将引发强大的保护性 RSV 免疫力。我们将采取综合措施，实现四个目标 具体目标：（1）利用结构研究来定义保护性RSV G蛋白表位所识别的保守RSV G蛋白表位。 抗体，(2) 使用结构引导设计来设计多聚 RSV G 蛋白免疫原，(3) 评估 工程化 RSV G 蛋白免疫原以提高免疫原性，以及 (4) 使用综合免疫 分析评估 RSV G 蛋白 CCD 免疫原的平衡细胞因子反应和保护性 因接种疫苗而产生的抗体。拟议的研究将产生 RSV G 疫苗免疫原 作为在预防 RSV 感染和疾病发病机制方面已被证明有效的候选者。