Structure-based Vaccine Design for CCHFV

项目摘要/摘要 克里米亚-刚果出血热病毒(CCHFV)在人类中引起一种威胁生命的壁虱传播疾病。 该病表现为一种严重的出血热，病死率为10%-40%。猪瘟病毒 疫情横跨广泛的地理区域，从西亚和中亚，中东， 非洲和南欧。全球气温上升、候鸟和国际牲畜 贸易都有可能导致肺透明线虫的传播--猪瘟病毒的主要传播媒介。 不断扩大的流行区、广泛的发病率和显著的死亡率使CCHFV成为对 公共卫生，因此被列为NIAID A类优先病原体。病毒基因组编码一种 糖蛋白前体，被加工成两种结构糖蛋白-Gn和GC-以及两种分泌的糖蛋白 糖蛋白-粘蛋白样域和GP38。已分离出保护性抗体，可靶向GC或 Gp38，提示这两种蛋白应优先用于疫苗开发。在这里我们 建议设计基于GC和GP38的免疫原，将免疫反应集中在广泛的 能够引起保护性抗体反应的保守表位。为了实现我们的目标，我们 将从结构上表征CCHFV糖蛋白及其与人源性抗体的相互作用， 部分根据结构信息合理设计疫苗抗原，并表征 在动物模型中由这些抗原引起的免疫反应。这些结果将用来指导进一步的 免疫原的改进，包括展示自组装的多价纳米粒子，以及 最有希望的候选者将在CCHFV挑战的致死小鼠模型中进行评估。鉴于我们的 专业知识、独特的试剂和初步数据，我们有信心提供最先进的 有可能诱导交叉反应保护性抗体的候选亚单位疫苗，从而 满足对这种NIAID A类扁虱传播病原体的未得到满足的需求。

Project Summary/Abstract Crimean-Congo hemorrhagic fever virus (CCHFV) causes a life-threatening tick-borne disease in humans. The disease presents as a severe form of hemorrhagic fever with a case fatality rate of 10–40%. CCHFV outbreaks have spanned a wide geographic area ranging from Western and Central Asia, the Middle East, Africa and Southern Europe. Increasing global temperatures, migratory birds, and the international livestock trade have all potentially contributed toward the spread of Hyalomma ticks—the primary vector for CCHFV. Expanding endemic zones, widespread morbidity and significant mortality make CCHFV an acute threat to public health and thus is listed as a NIAID Category A priority pathogen. The viral genome encodes a glycoprotein precursor that is processed into two structural glycoproteins—Gn and Gc—and two secreted glycoproteins—a mucin-like domain and GP38. Protective antibodies have been isolated that target Gc or GP38, suggesting that these two proteins should be given priority for vaccine development. Here we propose to engineer Gc- and GP38-based immunogens that focus the immune response onto broadly conserved epitopes that are capable of eliciting protective antibody responses. To accomplish our goal, we will structurally characterize CCHFV glycoproteins and their interactions with human-derived antibodies, rationally engineer vaccine antigens based in part on the structural information, and characterize the immune responses elicited by these antigens in animal models. These results will be used to guide further improvements of the immunogens, including display on self-assembling multi-valent nanoparticles, and the most promising candidates will be evaluated in a lethal murine model of CCHFV challenge. Given our expertise, unique reagents, and preliminary data, we are confident that we can deliver a state-of-the-art subunit vaccine candidate with the potential to induce cross-reactive protective antibodies, thereby satisfying an unmet need against this NIAID Category A tick-borne pathogen.