Preclinical Development of a Crimean-Congo Hemorrhagic Fever Virus Vaccine

克里米亚-刚果出血热病毒疫苗的临床前开发

• 批准号: 10655324
• 负责人: Thomas William Geisbert
• 金额: $ 73.99万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655324
• 关键词: Advanced Development; Africa; Animal Model; Animals; Applications Grants; Arboviruses; Attenuated; Biological Assay; Biological Products; Biological Sciences; Biology; Bioterrorism; Category A pathogen; Clinical Treatment; Cluster randomized trial; Containment; Country; Crimean Hemorrhagic Fever; Crimean-Congo Hemorrhagic Fever Virus; Cyclic GMP; Dengue Virus; Disease; Disease Outbreaks; Dose; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Effectiveness; GTP-Binding Proteins; Generations; Genomic Segment; Geography; Glycoproteins; Goals; Guinea; HIV Vaccine Trials Network; HIV vaccine; Head; Health Personnel; Human; Immunization; Knockout Mice; Laboratories; Lassa virus; Lead; Licensing; Life; Macaca fascicularis; Marburgvirus; Medical; Modeling; Mus; National Institute of Allergy and Infectious Disease; National Security; Nature; Pathogenicity; Pharmaceutical Preparations; Phase; Preventive vaccine; Public Health; Recombinant Vaccines; Recombinants; Reporter; Research; Research Personnel; Surface; Treatment Protocols; United States Food and Drug Administration; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral Hemorrhagic Fevers; Virulence; Virus; Virus Diseases; World Health Organization; bioweapon; cross immunity; design; emerging pathogen; high risk; immunogenic; immunogenicity; lead candidate; manufacture; medical countermeasure; neurovirulence; next generation; nonhuman primate; open label; pre-clinical; preclinical development; prevent; protective efficacy; prototype; research and development; tick-borne; tick-borne virus; vaccine candidate; vaccine delivery; vaccine development; vaccine immunogenicity; vaccine trial; vector; vector vaccine

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.

项目概要/摘要 克里米亚-刚果出血热病毒 (CCHFV) 是一种蜱传新发病原体，可导致严重和严重的出血热。 在包括 30 多个国家的广泛地理范围内，人类经常患上致命的出血热。 NIAID 将 CCHFV 列为 A 类优先病原体，这是一种对人类造成最高风险的生物制剂。 CCHF 对公共健康特别重要，因为它没有获得许可。 可用于人类的疫苗或治疗方法，并且由于担心该病毒可能被用作 该项目的目标是推进重组疫苗的开发。 基于表达 CCHFV 糖蛋白的下一代水泡性口炎病毒 (rVSV) 载体 潜在的医疗对策可以为 CCHFV 的所有六个遗传上不同的分支提供保护。 该申请旨在开发下一代 rVSV 载体 CCHF 疫苗并进行临床前验证。 Vesiculovax™ CCHF 疫苗将与已上市的原型 rVSV 疫苗进行直接比较 将比较显示能完全保护动物免受致命性 CCHFV 感染的疫苗。 免疫原性、缺乏神经毒力以及保护 STAT-1 敲除小鼠免受所有六种 M 的能力 然后将使用以下方法筛选出 CCHFV 的主要候选疫苗来支持研究。 新开发的CCHFV致死性非人灵长类动物模型将用于确认CCHFV的保护功效 主要候选疫苗，评估疫苗提供快速保护的能力，最后开始 该提案将汇集疫苗开发、CCHFV 方面的专业知识。 开发既能应对疫情又能应对生物武器的疫苗需要生物学和动物模型 需要通过单次管理快速保护所有 CCHFV 分支的场景。