Development of VPL Vaccine for RSV

项目摘要 人类呼吸道合胞病毒(RSV)被认为是引起急性呼吸道感染的最重要的病毒原因。 全世界婴幼儿中的呼吸系统疾病。老年人口和免疫功能受损 个人患严重呼吸道合胞病毒病的风险也很大。尽管这种疾病负担非常大 由于呼吸道合胞病毒在全球范围内的强加，目前还没有疫苗可用。几个问题阻碍了RSV疫苗的接种 发展。首先是安全问题。早期福尔马林灭活疫苗(FI-RSV)使婴儿容易患上更多 由于自然暴露于活病毒而导致的严重疾病，导致对所有人随后的安全的担忧 开发了RSV疫苗，特别是非复制型疫苗。第二个问题是缺乏对 对刺激保护性反应的要求使得新候选疫苗的效力难以预测。 第三个问题是RSV感染以及许多候选疫苗未能刺激长期免疫， 保护性免疫反应。 这项提议旨在检验一种假设，即新型病毒样颗粒(VLP)RSV疫苗 与之前测试的任何候选疫苗不同，候选疫苗可能会被开发成RSV疫苗。公布的结果表明 表达RSV糖蛋白的新城疫VLP是非常有效和安全的疫苗，可以刺激 小鼠系统中非常持久的保护性反应。该项目将进一步发展这些VLP作为RSV 候选疫苗。该项目将测试不同构象形式的RSV F蛋白的假设 影响抗RSV免疫反应的特性。目的是鉴定RSV F的构象 VLP上表达的一种蛋白，能刺激高滴度中和抗体和保护性的、长寿的和 记忆免疫反应，并测试选定的候选疫苗在棉鼠身上的有效性和安全性。 具体目标1：确定中和抗体效价和抵抗RSV攻击的保护水平 由三种不同的第二代VLP候选疫苗在小鼠身上刺激。 具体目的2：评价精选VLP免疫小鼠后的安全性。 具体目标3：评估选定的VLP在棉花免疫后提供的安全性和保护 老鼠。

Project Summary Human respiratory syncytial virus (RSV) is recognized as the single most important viral cause of acute respiratory disease in infants and young children worldwide. Elderly populations and immunocompromised individuals are also at significant risk for serious RSV disease. Despite this very substantial disease burden imposed by RSV worldwide, there are no vaccines available. Several problems have impeded RSV vaccine development. First is safety. An early formalin-inactivated vaccine (FI-RSV) predisposed infants to more severe disease upon natural exposure to live virus resulting in concerns about the safety of all subsequently developed RSV vaccines, particularly nonreplicating vaccines. A second problem is a lack of understanding of requirements for stimulation protective responses making efficacy of new vaccine candidates difficult to predict. A third problem is the failure of RSV infections as well as many vaccine candidates to stimulate long-term, protective immune responses. This proposal is designed to test the hypothesis that novel virus-like particle (VLP) RSV vaccine candidates, unlike any previously tested, may be developed into an RSV vaccine. Published results indicate that Newcastle disease VLPs expressing RSV glycoproteins are very effective and safe vaccines that stimulate very durable protective responses in a murine system. This project will further develop these VLPs as RSV vaccine candidates. This project will test the hypothesis that different conformational forms of RSV F protein impact the properties of anti-RSV immune responses. The goal is to identify the conformation of RSV F protein, expressed on VLPs, that stimulate high titer neutralizing antibodies and protective, long-lived and memory immune responses and to test the efficacy and safety of selected vaccine candidates in cotton rats. Specific Aim 1: to determine neutralizing antibody titers and levels of protection from RSV challenge stimulated in mice by three different second generation VLP vaccine candidates. Specific Aim 2: to assess the safety afforded by selected VLPs after immunization of mice. Specific Aim 3: to assess the safety and protection afforded by a selected VLPs after immunization of cotton rats.