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

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 它也是老年人和免疫功能低下人群发病的主要原因。 目前尚无获批的RSV疫苗。我们的目标是利用结构导向的设计方法， 工程化RSV G蛋白免疫原，其诱导针对RSV的安全和保护性免疫。RSV G蛋白是 RSV表面两种主要免疫原性蛋白之一，在病毒附着于气道中起关键作用 上皮细胞和先天免疫防御的病毒调节。RSV G蛋白是广泛的 中和，保护性抗体，但其作为疫苗免疫原的发展受到阻碍， 安全性问题与其对趋化因子受体CX 3CR 1+细胞的免疫调节活性有关， 表位的结构信息。在这个提议中，我们将测试我们的中心假设， 不能激活CX 3CR 1+细胞但显示保护性构象表位的RSV G免疫原 将引发安全有效的RSV免疫。我们将使用一种综合的、多学科的方法， RSV G蛋白结构与工程（DuBois）和RSV病毒学与免疫学（Tripp）攻读四 具体目的：（1）使用结构研究来确定RSV G蛋白的保守表位， 保护性抗体和趋化因子受体CX 3CR 1的结合位点，（2）使用结构导向设计 （3）采用多参数免疫学方法， 用于改善安全性和免疫原性的工程化RSV G蛋白免疫原，和（4）评价2-3 本发明提供了工程化的RSV G蛋白免疫原，用于在小鼠中预防RSV感染和疾病的安全性和能力。 拟议的研究将产生一种单一的工程化RSV G疫苗免疫原， 在体内预防RSV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.