Research Project 1: Vaccine for Rapid Response to Filovirus Outbreak

项目总结/摘要-研究项目1 埃博拉病毒（Ebola virus，EBOV）和马尔堡病毒（Marburg virus，MARV 代表组成丝状病毒科的两个属的病毒。马尔堡病毒属包含一个 种（MARV），而埃博拉病毒属由五种公认的种组成：苏丹埃博拉病毒（SUDV）， 扎伊尔埃博拉病毒（EBOV）、塔伊森林埃博拉病毒（TAFV）、莱斯顿埃博拉病毒（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， EBOV，MARV高达90%，SUDV约为55%，BDBV为25-50%。这些特工是机密 被NIAID/NIH和CDC列为A类优先病原体，目前没有许可的活性或 被动干预措施，用于自然爆发、实验室事故或故意滥用造成的接触。 公共卫生问题是基于这些病毒的新出现的传染病状态及其 可能用作生物武器。一种有效的预防性疫苗将在医疗领域得到应用。 在撒哈拉以南非洲流行地区暴发期间， 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接触。的 一种理想的疫苗，以满足爆发和生物武器的情况下，将迅速提供保护， EBOV和MARV的单次剂量。在测试单剂量保护的疫苗策略中， 最成功的是基于水泡性口炎病毒（VSV）的载体疫苗。进行性 撒哈拉以南非洲的城市化增加了丝状病毒感染者进入非洲的可能性。 在人口密度高的地区，无论是在不知情的情况下还是在寻求医疗救助的情况下。正如最近在西非 疫情爆发后，城市中心内部和之间的流动性增加， 病例的地理分布。因此，在没有广泛预防性免疫的情况下， 预防丝状病毒的疫苗的有效使用将保护医护人员和阻止传播 使用“环疫苗”。第一个应用程序是由辅助的，第二个应用程序是依赖于，快速 保护的开始。根据NIAID合同HHSN 272201700077 C资助的工作支持开发 EBOV、SUDV和MARV的疫苗，用rVSVN 4CT 1作为载体，rVSVN 4CT 1是一种减毒活VSV载体， 在多项临床试验中证明安全。本申请提出开发rVSVN 4CT 1矢量化BDBV 疫苗通过MVS生产和IND使能毒理学试验，以确定保护作用的起效时间 由针对最受关注的四种丝状病毒物种（EBOV，SUDV， BDBV和MARV）。此外，它建议解决有关疫苗效价提供的问题， 在快速反应环境中使用的最有效的配方。

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.