Development of vaccines targeting a tick-borne phlebovirus

严重发热伴血小板减少综合征病毒（SFTSV）是一种由蜱传播的致病性 布尼亚病毒，可导致严重的发热性腹泻样疾病，病死率为 高达30%。在2009年中国爆发发热性疾病期间发现， SFTSV的分布扩展到韩国和日本，最近有越南感染的报告 和俄罗斯SFTSV的蜱虫媒介在整个亚洲广泛传播。众多国内和 野生动物自然感染SFTSV，表明存在潜在溢出的大型水库 对人类目前没有SFTSV的疫苗或治疗剂。因为它的流行 世界卫生组织将SFTSV列入其2017年的建议“研究和开发 预防流行病的行动蓝图”，并将SFTSV确定为最常见的11种病原体之一。 可能在不久的将来引起严重的疫情，并建议开发疫苗。这里 我们将探索SFTSV疫苗的两种互补和潜在的协同策略： 重组病毒载体和编码SFTSV病毒的核苷修饰的mRNA 糖蛋白水泡性口炎病毒（VSV）是一种细胞病变病毒， 由于其能够快速诱导强的保护性抗体和T细胞， 在单剂量后对编码的外来抗原的应答。使用表达VSV载体， SFTSV病毒糖蛋白（类似于目前使用的VSV-埃博拉疫苗），我们 证明单次给药诱导中和抗体应答和保护 IFNAR 1敲除小鼠模型中的SFTSV攻击。另外，我们表明接种疫苗 单剂量核苷修饰的mRNA脂质纳米粒（mRNA-LNP） 编码SFTSV糖蛋白的抗体产生高水平的SFTSV中和抗体， 当转移到IFNAR 1 KO模型中时，能够赋予部分SFTSV保护。 基于这些强有力的初步研究结果，我们建议表征抗体和T细胞 当这些疫苗单独使用或与其他疫苗一起使用时，rVSV和mRNA接种的小鼠中的应答 预充-加强方案这些研究意义重大，因为对 这种高致病性病毒的疫苗（一份报告）以及rVSV和mRNA在 初免-加强疫苗接种尚未报道。最后，目前SFTSV的小动物模型 感染仅限于I型IFN应答被敲除的动物。因为这些动物 缺乏支持细胞扩增的重要先天免疫应答机制， 和体液免疫反应，我们将开发一种免疫能力强的小鼠疫苗， 在SFTSV攻击期间使用瞬时单克隆抗体阻断IFNAR 1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.