PRE-CLINICAL TESTING OF FILOVIRUS VACCINES IN NONHUMAN PRIMATES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 丝状病毒科的成员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年就会定期爆发。这是一种A类制剂，需要在最大限度的控制下进行操作。在野外，感染始于人们与死亡或垂死的受病毒感染的森林动物接触，如黑猩猩，森林羚羊和豪猪，这些动物经常在受影响地区的雨林地面上发现。扎伊尔型埃博拉病毒最常与死亡率极高的疫情相关，平均死亡率在80%至90%之间。除了治标措施外，没有有效的治疗方法。 迄今为止，没有商业疫苗可用于保护免受丝状病毒感染。在昆虫细胞培养系统中表达的埃博拉扎伊尔病毒的三种重组亚单位蛋白的免疫原性先前在小鼠中进行了评价。这些实验是成功的，并导致选择了在活病毒攻击实验（在USAMRlID）中进一步测试的疫苗制剂。有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有完全的保护作用。非人灵长类动物在丝状病毒感染后显示出与人类相似的病程，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）中成功证明了针对扎伊尔型埃博拉病毒的免疫原性和有效性后，因此必须在非人灵长类动物中评价主要候选疫苗的免疫原性和针对活病毒攻击的保护潜力。如果在用新疫苗免疫后可以证明相关的免疫应答（抗体和成熟淋巴细胞），则该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，以实现临床试验的目标。

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.