Development of vaccines targeting a tick-borne phlebovirus

严重发烧伴血小板减少综合征病毒(SFTSV)是一种由壁虱传播的病原性病毒 可导致严重发烧出血性疾病的布尼亚病毒，病死率为 高达30%。在2009年中国的一次发烧期间被发现，地理位置 流行性出血热病毒的分布扩展到韩国和日本，最近有越南感染的报告 还有俄罗斯。猪瘟的森林媒介在整个亚洲都很普遍。众多国内和 野生动物自然感染SFTSV，这意味着一个具有潜在溢出效应的大型水库 对人类来说。目前还没有针对SFTSV的疫苗或疗法。因为它的流行 威胁世界卫生组织将SFTSV纳入其2017年的建议 《预防疫情行动蓝图》，并将SFTSV确定为最多的11种病原体之一 可能在不久的将来造成严重暴发，并提议开发疫苗。这里 我们将探索SFTSV疫苗的两种互补和潜在的协同策略： 编码SFTSV病毒的重组病毒载体及核苷修饰的mRNA 糖蛋白。水疱性口炎病毒(VSV)是一种细胞病变病毒，已发展为 一种疫苗载体，因为它能够快速诱导强大的保护性抗体和T细胞 对编码的外来抗原在单次剂量后的反应。使用VSV向量来表达 SFTSV病毒糖蛋白(类似于目前使用的VSV-埃博拉疫苗)，我们 演示单剂诱导中和抗体反应并保护 在IFNAR1基因敲除小鼠模型中的SFTSV挑战。另外，我们表明，接种疫苗 核苷修饰的信使核糖核酸脂质纳米粒(MRNALNP)对WT小鼠的影响 编码SFTSV糖蛋白可诱导高水平的SFTSV中和抗体，这些抗体是 当转换到IFNAR1 KO型号时，能够提供部分SFTSV保护。 基于这些强有力的初步发现，我们建议将抗体和T细胞 RVSV和mRNA疫苗单独使用或联合应用时小鼠的免疫应答 最佳强化养生法。这些研究具有重要意义，因为人们对 这种高致病性病毒的疫苗(单一报告)和rVSV和mRNA在中国的应用 还没有关于Prime-Boost疫苗接种的报道。最后，目前SFTSV的小动物模型 感染仅限于I型干扰素反应被剔除的动物。因为这些动物 缺乏支持细胞扩增的重要先天免疫反应机制 和体液免疫反应，我们将开发一种免疫能力强的小鼠疫苗 SFTSV攻击过程中瞬时阻断IFNAR1的模型。

Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) is a pathogenic, tick-transmitted bunyavirus that can cause a severe febrile hemorrhagic-like disease with case fatality rates of up to 30%. Discovered during a 2009 outbreak of febrile illness in China, the geographic distribution of SFTSV extends into Korea and Japan with recent reports of infection in Vietnam and Russia. The tick vector for SFTSV is widespread throughout Asia. Numerous domestic and wild animals are naturally infected by SFTSV suggesting a large reservoir with potential spillover to humans. There are currently no vaccines or therapeutics for SFTSV. Because of its epidemic 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. Here we will explore two complementary and potentially synergistic strategies for an SFTSV vaccine: a recombinant viral vector and nucleoside-modified mRNA encoding the SFTSV viral glycoproteins. Vesicular stomatitis virus (VSV) is a cytopathic virus that has been developed as a vaccine vector due to its ability to rapidly induce strong, protective antibody and T cell responses to encoded foreign antigens after a single dose. Using a VSV vector expressing the SFTSV viral glycoproteins (similar to the currently employed VSV-Ebola vaccine), we demonstrate single dose induction of a neutralizing antibody response and protection from SFTSV challenge in an IFNAR1 knockout mouse model. Separately, we show that vaccination of wt mice with a single dose of nucleoside-modified mRNA lipid nanoparticles (mRNA-LNP) encoding the SFTSV glycoproteins elicits high levels of SFTSV neutralizing antibodies that are capable of conferring partial SFTSV protection when transferred into the IFNAR1 KO model. Based upon these strong preliminary findings we propose to characterize antibody and T-cell responses in rVSV and mRNA vaccinated mice when these vaccines are used alone or in a prime-boost regimen. These studies are significant as there is limited knowledge regarding vaccines for this highly pathogenic virus (a single report) and use of rVSV and mRNA in a prime-boost vaccination has not been reported. Finally, current small animal models of SFTSV infection are limited to animals with type I IFN responses knocked out. Because these animals lack an important innate immune response mechanism that supports amplification of cellular and humoral immune responses, we will develop an immune competent mouse vaccination model using transient monoclonal antibody blockade of IFNAR1 during SFTSV challenge.