A VSV vectored vaccine for emergent tick-born phleboviruses

水疱性口炎病毒(VSV)是一种细胞病变病毒，已被开发为疫苗 载体由于其能够诱导编码的强大的保护性抗体和T细胞反应 单次给药后出现外来抗原。VSV有效地结合了糖蛋白( GP)来自 病毒粒子表面的不同病毒允许生产具有复制能力的重组 其中同源VSV G基因被外源GP基因取代的载体。 重组变速箱 表达外源gp的rVSVs已被用作多种病原体的疫苗载体。 包括最近成功部署的rVSV-埃博拉疫苗。尽管取得了这样的成功， 在动物模型中的研究表明，当注射一些rVSV时，会产生显著的致病效应 在大脑内或在用于感染有缺陷的干扰素反应的动物时。令人担忧的问题 由这些研究提出支持开发更弱的rVSV载体，具有更好的安全性 配置文件。特殊目标1将利用一种新的策略来减毒rVSV疫苗载体，方法是 使用P2A核糖体跳过序列连接相邻的VSV转录本 VSV基因组中的基因。将检测具有单个或多个融合转录本的rVSV 免疫低下小鼠模型或中枢神经系统的发病机制。在具体目标2中 表达重症发热病毒糖蛋白的下一代低致病力载体 将分析血小板减少综合征病毒(SFTSV)的诱导能力 中和反应。SFTSV是一种由壁虱传播的致病性本雅氏病毒，可引起 严重发热出血性疾病，病死率高达30%。最初发现 2009年中国热病暴发期间，猪瘟病毒的地理分布扩大 进入韩国和日本。目前还没有针对SFTSV的疫苗或疗法。因为它的 潜在威胁世界卫生组织将SFTSV纳入其2017年的建议 预防流行病的行动蓝图“，并将SFTSV确定为11种病原体之一 最有可能在不久的将来造成严重暴发，并提议开发疫苗。 这份修订后的申请中包括了初步数据，证明了强诱导 小鼠中和抗体应答与对SFTSV攻击的保护作用 接种第一代rVSV-SFTSV。此外，对IFNAR-/-小鼠进行疫苗接种 第一代rVSV-SFTSV表现出显著的病理变化(体重减轻)，支持 目标1的前提。这个简短的想法建议旨在产生衰减的rVSV向量 对许多病原体的疫苗开发很有用，并将生成原理证明数据 这将允许进一步开发SFTSV疫苗。

Vesicular stomatitis virus (VSV) is a cytopathic virus that has been developed as a vaccine vector due to its ability to induce strong, protective antibody and T cell responses to encoded foreign antigens after a single dose. VSV efficiently incorporates glycoproteins ( GP) from a different virus on virion surface allowing production of replication-competent recombinant vectors in which the cognate VSV G gene is replaced by a foreign GP gene. Recombinant VSVs (rVSVs) expressing foreign GPs have been studied as vaccine vectors for a number of pathogens including the recent successful deployment of a rVSV-Ebola vaccine. Despite this success, studies in animal models demonstrate significant pathogenic effects when some rVSV are injected intracerebrally or when used to infect animals with defective interferon responses. Concerns raised by these studies support development of more attenuated rVSV vectors with better safety profiles. Specific Aim 1 will utilize a novel strategy for attenuating rVSV vaccine vectors by joining adjacent VSV transcripts using a P2A ribosomal skipping sequence between adjacent genes in the VSV genome. rVSV with single or multiple fused transcripts will be tested for pathogenesis in immunocompromised mouse models or in the CNS. In Specific Aim 2 these next generation, low pathogenicity vectors expressing the glycoproteins of Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) will be analyzed for their ability to induce neutralizing responses. SFTSV is a pathogenic, tick-transmitted bunyaviruses that causes a severe febrile hemorrhagic-like disease with case fatality rates of up to 30%. Initially discovered during a 2009 outbreak of febrile illness in China, the geographic distribution of SFTSV extends into Korea and Japan. There are currently no vaccine or therapeutics for SFTSV. Because of its potential threat the WHO included SFTSV in its 2017 recommendation “A research and development Blueprint for action to prevent epidemics” and identified SFTSV as one of 11 pathogens most likely to cause severe outbreaks in the near future and proposed development of vaccines. Included in this revised application are preliminary data demonstrating induction of strong neutralizing antibody responses that correlate with protection from SFTSV challenge in mice vaccinated with a 1st generation rVSV-SFTSV. Additionally, vaccination of IFNAR-/- mice with the 1st generation rVSV-SFTSV demonstrated significant pathology (weight loss) supporting the premise for Aim 1. This short IDEA proposal is designed to produce attenuated rVSV vectors useful for vaccine development for many pathogens and will generate proof-of-principle data that will permit further development of a vaccine for SFTSV.