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

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 其对趋化因子受体CX3CR1细胞的免疫调节活性和缺乏 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 不能激活CX3CR1细胞但显示保护性构象表位的RSV G免疫原 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。

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.