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

项目摘要 呼吸道合胞病毒（RSV）是导致年轻人严重下呼吸道疾病的主要原因 也是老年人发病和部分死亡的主要原因， 免疫力低下目前尚无获批的RSV疫苗。我们的目标是利用结构导向设计 一种合理工程化RSV G蛋白免疫原的方法， RSV。RSV G蛋白是RSV表面的两种主要免疫原性蛋白之一，在病毒的免疫应答中起着关键作用。 附着于气道上皮细胞和先天免疫防御的病毒调节。RSV G蛋白是 中和和保护性抗体的靶点。G蛋白作为疫苗免疫原受到以下因素的阻碍： 免疫原性差和缺乏关于其表位的结构信息。在本提案中，我们将测试我们的 中心假设，工程化的多聚体RSV G免疫原， 表位将引发稳健的和保护性的RSV免疫。我们将采用综合方法， 具体目的：（1）利用结构研究来确定RSV G蛋白的保守表位， 抗体，（2）使用结构导向设计来工程化多聚体RSV G蛋白免疫原，（3）评估 工程化的RSV G蛋白免疫原，用于改善免疫原性，和（4）使用全面的免疫原性， 分析以评估RSV G蛋白CCD免疫原的平衡细胞因子应答和保护性免疫应答。 免疫后产生的抗体。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中显示功效的候选物。

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.