PRE-CLINICAL TESTING OF FILOVIRUS VACCINES IN NONHUMAN PRIMATES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 丝状病毒科的成员会在人类和非人类灵长类动物中引起严重的出血热。最突出的成员是埃博拉病毒，自1976年首次发现以来，每隔2-10年定期爆发一次。它是一种A类特工，需要在最大程度上进行控制。在野外，感染源于接触死亡或濒临死亡的受病毒感染的森林动物，如黑猩猩、森林羚羊和豪猪，这些动物经常在受影响地区的热带雨林地面上发现。扎伊尔埃博拉病毒株最常与高死亡率的疫情有关，平均死亡率在80%至90%之间。除了治标不治本外，目前还没有有效的治疗方法。 到目前为止，还没有商业疫苗可以预防丝状病毒的感染。此前，在昆虫细胞培养系统中表达的三种重组埃博拉扎伊尔病毒亚单位蛋白在小鼠身上进行了免疫原性评估。这些实验是成功的，并导致了疫苗配方的选择，这些疫苗配方已经在活病毒挑战实验中进一步测试(在USAMRlID)。几种制剂对同源病毒株(扎伊尔埃博拉病毒)引起的发病率和死亡率具有完全保护作用。非人灵长类动物在感染丝状病毒时表现出与人类相似的疾病过程，因此被认为是最能预测人类疗效的模型。在两种啮齿动物模型(小鼠和豚鼠)上成功证明了对埃博拉扎伊尔病毒的免疫原性和有效性后，因此必须评估领先的候选疫苗在非人类灵长类动物中的免疫原性和抵抗活病毒攻击的保护潜力。如果用新型疫苗免疫后能够表现出相关的免疫反应(抗体和成熟的淋巴细胞)，本实验将为该技术提供关键的概念验证。这项研究的成功完成将提前验证埃博拉疫苗制剂的有效性，从而达到临床测试的目标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Members of the family Filoviridae cause severe hemorrhagic fevers in humans and nonhuman primates. The most prominent member, Ebola virus, causes outbreaks periodically at 2-10 year intervals since initial identification in 1976. It is a Category A agent and requires manipulation at maximum containment. In the wild, infections initiate from contact of people with dead or dying virus-infected forest animals such as chimpanzees, forest antelope and porcupines that have been regularly found on the rainforest floor in affected areas. The Zaire strain of Ebola is most often associated with outbreaks with very high mortality rates, on average between 80 to 90%. Apart from palliative measures, there is no effective treatment for the disease. To date, no commercial vaccine is available to protect against infection with filoviruses. The immunogenicity of three recombinant subunit proteins of Ebola Zaire virus expressed in an insect cell culture system was previously evaluated in mice. The experiments were successful and led to the selection of vaccine formulations that have further been tested in a live virus challenge experiment (at USAMRlID). Several formulations elicited complete protection against morbidity and mortality caused by the homologous virus strain (Ebola Zaire). Nonhuman ,primates show a similar course of disease upon filovirus infection as humans and are therefore considered to be the model most predictive of human efficacy. After successful demonstration of immunogenicity and efficacy against Ebola Zaire virus in two rodent models (mice and guinea pigs), the leading vaccine candidates therefore have to be evaluated for immunogenicity and protective potential against live virus challenge in non-human primates. If relevant immune responses (antibody and mature lymphocytes) can be demonstrated after immunization with the novel vaccines, this experiment will provide the pivotal proof-of-concept for the technology. Successful completion of this study will validate the efficacy of the Ebola vaccine preparations in advance to the goal of clinical testing.