Research Project 1: Vaccine for Rapid Response to Filovirus Outbreak

研究项目1：快速应对丝状病毒爆发的疫苗

• 批准号: 10576279
• 负责人: Stefan L Hamm
• 金额: $ 76.18万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576279
• 关键词: Research; Project; Vaccine; Rapid; Response

PROJECT SUMMARY/ABSTRACT – Research Project 1 Ebola virus (EBOV) and Marburg virus (MARV) are filamentous enveloped non-segmented negative sense RNA viruses representing the two genera that comprise the family Filoviridae. The Marburgvirus genus contains one species (MARV), while the Ebolavirus genus is comprised of five recognized species: Sudan ebolavirus (SUDV), Zaire ebolavirus (EBOV), Tai Forest ebolavirus (TAFV), Reston ebolavirus (RESTV), and Bundibugyo ebolavirus (BDBV). These viruses are important human pathogens with case fatality rates ranging from 70% to 90% for EBOV, up to 90% for MARV, approximately 55% for SUDV, and 25-50% for BDBV. These agents are classified as Category A Priority Pathogens by the NIAID/NIH and CDC, and there are presently no licensed active or passive interventions for exposure resulting from natural outbreak, laboratory accident, or deliberate misuse. The public health concern is based on both the emerging infectious disease status of these viruses and their potential use as biologic weapons. An effective prophylactic vaccine would find application with medical personnel and close contacts during outbreaks in endemic areas of sub-Saharan Africa, with laboratory workers engaged in filovirus research, and with military and civilian personnel threatened by weaponized filoviruses. The ideal vaccine to meet both the outbreak and bioweapon scenarios would rapidly confer protection against all species of EBOV and MARV with a single dose. Among the vaccine strategies tested for single dose protection, the most successful have been vectored vaccines based on vesicular stomatitis virus (VSV). The progressing urbanization of sub-Saharan Africa has increased the probability that a filovirus infected individual will enter an area of high population density either unknowingly or to seek medical aid. As seen in the recent west African outbreak, the increased mobility within and between the urban centers can rapidly expand the number and geographic distribution of cases. Thus, in the absence of widespread prophylactic immunization, the most effective uses of a vaccine against the filoviruses will be protection of healthcare workers and breaking spread using ‘ring vaccination’. The first application is aided by, and the second application is dependent upon, a rapid onset of protection. Funded work under NIAID contract HHSN272201700077C supports development of vaccines for EBOV, SUDV, and MARV that are vectored with rVSVN4CT1, a live attenuated VSV vector that has proven safe in multiple clinical trials. This application proposes to develop an rVSVN4CT1-vectored BDBV vaccine through MVS production and IND-enabling toxicology testing, to establish the time to onset of protection provided by rVSVN4CT1-vectored vaccines against the four filovirus species of greatest concern (EBOV, SUDV, BDBV, and MARV). In addition, it proposes to address the questions regarding the vaccine valency providing the most effective formulation for use in a rapid response setting.

项目摘要/摘要 – 研究项目 1 埃博拉病毒 (EBOV) 和马尔堡病毒 (MARV) 是丝状包膜非节段负义 RNA 代表构成丝状病毒科的两个属的病毒 马尔堡病毒属包含一种。 种 (MARV)，而埃博拉病毒属由五个公认的种组成：苏丹埃博拉病毒 (SUDV)、 扎伊尔埃博拉病毒 (EBOV)、泰森林埃博拉病毒 (TAFV)、雷斯顿埃博拉病毒 (RESTV) 和本迪布焦埃博拉病毒 (BDBV)。这些病毒是重要的人类病原体，病死率在 70% 至 90% 之间。 EBOV、MARV 高达 90%、SUDV 约 55%、BDBV 约 25-50%。 被 NIAID/NIH 和 CDC 列为 A 类优先病原体，目前没有获得许可的活性或 对自然爆发、实验室事故或故意滥用造成的暴露进行被动干预。 公共卫生关注是基于这些病毒的新出现的传染病状况及其 一种有效的预防性疫苗将在医疗领域得到应用。 撒哈拉以南非洲流行地区疫情爆发期间的人员和密切接触者，以及实验室工作人员 从事丝状病毒研究，并与受到武器化丝状病毒威胁的军事和文职人员合作。 满足爆发和生物武器情况的理想疫苗将迅速预防所有疾病 在针对单剂量保护进行测试的疫苗策略中， 最成功的是基于水疱性口炎病毒（VSV）的载体疫苗。 撒哈拉以南非洲的城市化增加了丝状病毒感染者进入城市的可能性 正如最近西非所见，人口密度高的地区要么不知不觉，要么寻求医疗援助。 疫情爆发后，城市中心内部和之间的流动性增加可以迅速扩大数量和 因此，在没有广泛预防性免疫接种的情况下，病例的地理分布最为严重。 有效使用丝状病毒疫苗将保护医护人员并阻止传播 使用“环形疫苗接种”，第一次应用需要快速疫苗接种，而第二次应用则依赖于快速疫苗接种。 NIAID 合同 HHSN272201700077C 资助的工作支持开发 以 rVSVN4CT1 为载体的 EBOV、SUDV 和 MARV 疫苗，rVSVN4CT1 是一种减毒活 VSV 载体，具有 经多项临床试验证明是安全的。本申请建议开发 rVSVN4CT1 载体 BDBV。 通过 MVS 生产和支持 IND 的毒理学测试来确定疫苗起效时间 rVSVN4CT1 载体疫苗提供针对最受关注的四种丝状病毒（EBOV、SUDV、 此外，它还建议解决有关疫苗效价的问题。 在快速反应环境中使用的最有效的配方。