Preclinical Development of a Crimean-Congo Hemorrhagic Fever Virus Vaccine

项目总结/摘要 克里米亚-刚果出血热病毒（CCHFV）是一种蜱传的新兴病原体，可引起严重的 在包括30多个国家的广泛地理范围内，人类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对公众健康特别重要，因为没有持牌的 疫苗或治疗可用于人类，因为担心该病毒可能被用作 生物恐怖分子的代理人该项目的目标是推进重组疫苗的开发 基于下一代水泡性口炎病毒（rVSV）载体， 潜在的医疗对策，可以提供保护所有六个遗传不同的分支的CCHFV。 本申请提出开发和临床前验证rVSV载体的CCHF疫苗。下一代 Vesiculovax™ CCHF疫苗将与已在临床试验的原型rVSV疫苗进行头对头比较。 完全保护动物免受致命的CCHFV感染。将比较疫苗 免疫原性，缺乏神经毒力，以及保护STAT-1敲除小鼠抵抗所有六种M CCHFV的片段分支。然后将向下选择主要候选疫苗。支持使用 新开发的致死性非人灵长类动物CCHFV模型将被用于证实 主要候选疫苗，评估疫苗提供快速保护的能力，最后开始 确定保护的相关因素。该提案将汇集疫苗开发、CCHFV 生物学和动物模型需要开发一种疫苗，以满足爆发和生物武器 需要通过单次给药快速防御所有CCHFV进化枝的场景。

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.