Preclinical Development of a Crimean-Congo Hemorrhagic Fever Virus Vaccine

项目摘要/摘要 克里米亚-刚果出血热病毒(CCHFV)是一种由壁虱传播的新出现的病原体，可引起严重和 在包括30多个国家在内的广泛地理范围内的人类中经常发生致命的出血热。 NIAID将CCHFV列为A类优先病原体，这是一种对 国家安全和公共卫生。CCHF对公共卫生特别重要，因为没有获得许可的 可供人类使用的疫苗或治疗方法，以及由于担心病毒可能被用作 生物恐怖主义的代理人。该项目的目标是推进重组疫苗的开发。 基于新一代水疱性口炎病毒(RVSV)载体将CCHFV糖蛋白表达为 潜在的医学对策，可以为CCHFV的所有六个不同的基因分支提供保护。 本申请建议开发一种rVSV载体CCHF疫苗并进行临床前验证。下一代 水痘™CCHF疫苗将与已经被证实的rVSV疫苗原型进行正面比较。 被证明能完全保护动物免受致命性CCHFV感染。疫苗将被比对为 免疫原性，缺乏神经毒力，以及保护STAT-1基因敲除小鼠免受所有六种M CCHFV的节段分支。然后将选出一种领先的候选疫苗。支持研究，使用 新开发的CCHFV致死性非人灵长类动物模型将用于证实 领先的候选疫苗，评估为疫苗提供快速保护的能力，最后开始 确定保护的相关因素。这项提案将汇集疫苗开发方面的专业知识，CCHFV 生物学和动物模型需要开发一种既能满足疫情爆发又能满足生物武器的疫苗 需要通过单一管理快速保护所有CCHFV分支的场景。

PROJECT SUMMARY/ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne emerging pathogen that causes severe and often fatal hemorrhagic fever in humans across a broad geographic range that includes more than 30 countries. The NIAID lists CCHFV as a Category A priority pathogen, a biological agent that poses the highest risk to national security and public health. CCHF is of particular importance to public health as there are no licensed vaccines or treatments available for use in humans, and because of the concern that the virus could be used as an agent of biological terrorism. The goal of this project is to advance the development of a recombinant vaccine based on next generation vesicular stomatitis virus (rVSV) vectors expressing the CCHFV glycoprotein as a potential medical countermeasure that can provide protection across all six genetically distinct clades of CCHFV. This application proposes to develop and pre-clinically validate a rVSV vectored CCHF vaccine. Next generation Vesiculovax™ CCHF vaccines will be compared head-to-head with a prototype rVSV vaccine that has been shown to completely protect animals against lethal CCHFV infection. Vaccines will be compared for immunogenicity, lack of neurovirulence, and the ability to protect STAT-1 knockout mice against all six M segment clades of CCHFV. A lead candidate vaccine will then be down selected. Supporting studies using a newly developed lethal nonhuman primate model of CCHFV will be employed to confirm protective efficacy of the lead vaccine candidate, assess the ability to the vaccine to provide rapid protection, and finally to begin to determine correlates of protection. This proposal will draw together expertise in vaccine development, CCHFV biology, and animal modeling needed to develop a vaccine that meets both the outbreak and bioweapon scenarios that require rapid protection against all CCHFV clades with a single administration.