A VSV vectored vaccine for emergent tick-born phleboviruses

水泡性口炎病毒（VSV）是一种细胞病变病毒，已被开发为疫苗 载体由于其诱导强的、保护性抗体和T细胞应答的能力， 单次注射后的外源抗原。VSV有效地整合糖蛋白（ GP）从A 病毒体表面上的不同病毒，允许产生有复制能力的重组体 其中同源VSV G基因被外源GP基因置换的载体。 重组VSV 已经研究了表达外源GP的rVSV作为许多病原体的疫苗载体 包括最近成功部署的rVSV埃博拉疫苗。尽管取得了成功， 在动物模型中的研究表明，当注射一些rVSV时， 脑内或当用于感染具有缺陷性干扰素应答的动物时。关切 这些研究提出的建议支持开发具有更好安全性的更弱的rVSV载体 数据区.特异性目标1将利用一种新的策略，通过以下途径减毒rVSV疫苗载体： 使用相邻VSV转录物之间的P2 A核糖体跳跃序列连接相邻VSV转录物， VSV基因组中的基因。将检测具有单个或多个融合转录物的rVSV， 在免疫受损小鼠模型或CNS中的发病机制。具体目标2 下一代低致病性载体，表达伴有严重发热的糖蛋白， 将分析血小板减少综合征病毒（SFTSV）诱导 中和反应。SFTSV是一种致病性蜱传布尼亚病毒， 严重的发热性腹泻样疾病，病死率高达30%。最初发现 在2009年中国发热性疾病爆发期间，SFTSV的地理分布范围扩大， 进入韩国和日本。目前没有SFTSV的疫苗或治疗剂。由于其 世界卫生组织在其2017年的建议中将SFTSV列入了“一项研究和 预防流行病行动发展蓝图”，并将SFTSV确定为11种病原体之一 最有可能在不久的将来引起严重疫情，并建议开发疫苗。 包括在这个修订后的申请是初步数据表明诱导强 中和抗体应答与保护小鼠免受SFTSV攻击相关 用第一代rVSV-SFTSV接种。另外，用以下疫苗接种IFNAR-/-小鼠： 第1代rVSV-SFTSV表现出显著的病理学（体重减轻），支持 目标1的前提。这个简短的IDEA提案旨在产生减毒的rVSV载体 可用于许多病原体的疫苗开发，并将产生原理证明数据 这将允许进一步开发SFTSV的疫苗。

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.