A Small Animal Model for Viscerotropic Disease to Improve Yellow Fever Vaccine

描述(申请人提供)：黄热病病毒(YFV)引起蚊媒疾病黄热病(YF)，这是一种嗜内脏疾病，即它以灵长类动物的肝脏为目标。这种疾病是由一种非常有效的减毒活疫苗17D株控制的，这种疫苗来自野生型菌株Asibi，在过去70年里已经为5.4亿人接种了疫苗。在过去的10年里，有报道称一种罕见但致命的疾病是由YF疫苗相关的嗜内脏疾病(Yel-AVD)疫苗引起的。这种情况与病毒在初级疫苗接种者中的不受控制的复制有关，导致了全身性感染和与野生型YFV非常相似的疾病图景。最初，据报道，耶尔-AVD的发病率为每10万名疫苗接种者中有0.3人。然而，2007年10月，秘鲁报告的发病率为每100,000人中有9人。这种令人震惊的严重不良事件正在导致监管当局重新评估17D疫苗的禁忌症和使用情况，一些人正在呼吁开发一种新的YF疫苗。然而，人们认识到，开发一种新疫苗至少需要15年时间。因此，迫切需要对目前的疫苗进行研究，以了解耶尔-AVD以及如何改进现有的疫苗。使用17D疫苗病毒产生嵌合病毒，在17D疫苗病毒主干中包含一种黄病毒(如乙型脑炎)的结构蛋白基因，强调了这一紧迫性。这种嵌合疫苗正在进行第二阶段的临床试验。令人惊讶的是，人们对野生型YFV毒力或YFV 17D减毒活疫苗的减毒和免疫原性的分子机制知之甚少。这在一定程度上是因为缺乏一种嗜内脏的小动物。PI已经开发出一种新的YFV感染模型，可以很容易地区分野生型Asibi毒株和17D疫苗毒株。我们的长期目标是使用这个模型来理解嗜内脏和减毒的免疫学基础。我们的具体目标是：i)研究与强毒Asibi病毒相比，弱毒17D病毒感染被阻断的致病序列中的步骤，从而识别可能对Yel-AVD的发展重要的先天免疫反应中的潜在异常；以及ii)通过在本项目开发的新的小鼠模型中检测Yel-AVD分离株的嗜内脏表型，鉴定Yel-AVD分离株中存在的YFV编码的嗜内脏分子决定因素。

DESCRIPTION (provided by applicant): Yellow fever virus (YFV) causes the mosquito-borne disease yellow fever (YF), a viscerotropic disease, i.e., it targets the liver, of primates. The disease is controlled by a very efficacious live attenuated vaccine, strain 17D, which was derived from wild-type strain Asibi and has been administered to over 540 million people in the last 70 years. In the last 10 years a rare, but fatal, condition has been reported due to the vaccine, termed YF vaccine associated viscerotropic disease (YEL-AVD). This condition is associated with uncontrolled replication of the virus in primary vaccinees resulting in pansystemic infection and a disease picture very similar to wild-type YFV. Originally, YEL-AVD was reported to have an incidence of 0.3 per 100,000 vaccinees. However, in October 2007, an incidence of 9 per 100,000 was reported in Peru. This alarming rate of serious adverse events is causing regulatory authorities to re-evaluate the contraindications and use of the 17D vaccine, and a number of individuals are calling for the development of a new YF vaccine. Nonetheless, it is recognized that development of a new vaccine takes at least 15 years. Thus, there is an urgent need to undertake research on the current vaccine to understand YEL-AVD and how the current vaccine could be improved. This urgency is emphasized by the use of 17D vaccine virus to generate chimeric viruses containing the structural protein genes of one flavivirus (e.g. Japanese encephalitis) in a 17D vaccine virus backbone. Such chimeric vaccines are in phase II clinical trials. Surprisingly, little is known about the molecular mechanisms that govern the virulence of wild-type YFV or the attenuation and immunogenicity of the live- attenuated YFV 17D vaccine. This is, in part, due to the lack of a small animal of viscerotropism. The PI has developed a new YFV infection model that readily distinguishes wild-type Asibi strain from the 17D vaccine strain. Our long-term goals are to use this model to understand the immunologic basis of viscerotropism and attenuation. Our specific aims are: i) investigate the steps in the pathogenic sequence at which attenuated 17D virus infection is blocked compared with virulent Asibi virus thereby identifying potential anomalies in the innate immune response that might be important to the development of YEL-AVD; and ii) identify YFV-encoded molecular determinants of viscerotropism present in YEL-AVD isolates by examining their viscerotropic phenotype in the new mouse model developed in this project.