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

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。 它也是老年人发病率和一些死亡率的主要原因。 免疫功能受损。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 合理设计RSV G蛋白免疫原诱导强健和保护性免疫的途径 RSV。RSV G蛋白是RSV表面的两种主要免疫原性蛋白之一，在病毒中起着关键作用 与呼吸道上皮细胞的附着和病毒对天然免疫防御的调节。RSV G蛋白是 中和性和保护性抗体的靶标。作为疫苗免疫原的G蛋白受到以下因素的阻碍 免疫原性差，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 设计具有保护性构象的多聚体RSV G免疫原的中心假设 表位将引发强大的和保护性的RSV免疫。我们将使用综合方法来实现四个目标 具体目的：(1)利用结构研究确定保护性识别的保守RSV G蛋白表位 抗体；(2)利用结构导向设计设计多聚体RSV G蛋白免疫原；(3)评价 工程RSV G蛋白免疫原用于提高免疫原性，以及(4)使用全面的免疫 呼吸道合胞病毒G蛋白免疫原平衡细胞因子应答及保护性分析 疫苗接种后产生的抗体。这项拟议的研究将产生RSV G疫苗免疫原 作为在预防RSV感染和疾病发病机制方面被证明有效的候选药物。

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.