MOP/LAS chimeric vaccine against Lassa fever

描述(申请人提供)：ArenaVirus是一种新出现的病原体，由啮齿动物携带，偶尔会传播给人类，造成致命后果。我们的研究主要集中在拉沙热病毒，因为它对人类的毒力。在西非，拉萨病毒每年造成30万人感染和数千人死亡。巨大的疾病负担和LAS病毒被用作生物战剂的可能性为有效的疫苗开发提供了强有力的理由。与小鼠中已有的ArenaVirus致病模型不同，拉沙热在人、豚鼠和非人类灵长类动物中的毒力与病毒血症直接相关，与免疫介导的病理关系较小。豚鼠是阐明拉萨病毒感染的发病机制以及疫苗和治疗发展的潜在有用的模型。莫佩亚病毒是拉沙热病毒的近亲，对豚鼠和猴子不是致死性的，可以保护它们免受拉沙病毒的攻击。为了确定Lassa病毒毒力的遗传基础，我们在Lassa(LAS)和Mopeia(MOP)病毒之间构建了异种病毒重组体。我们将检验这样的假设，即拉萨L RNA片段与实验动物的致死性急性疾病有关，并且由莫佩亚的L RNA和拉萨的S RNA组成的MOP/LAS重组病毒将是无毒的，并将提供有效的保护，使其免受致命的拉萨病毒的攻击。我们的具体目标将是：1)比较MOP/LAS和LAS/MOP重组病毒与两个亲本LAS和MOP病毒的毒力；2)测试MOP/LAS重组体保护豚鼠免受LAS病毒致命攻击的能力。毒力和保护性将通过存活率、病毒血症、组织中的病毒载量、临床化学和血液学紊乱来衡量。促炎细胞/趋化因子，如肿瘤坏死因子-α、白介素1-β、白介素6和白介素8，将被监测，因为临床和实验数据显示这些因素参与了LHF的发病。我们的长期目标是了解LAS病毒的发病机制，并开发有效的治疗方法和疫苗。

DESCRIPTION (provided by applicant): Arenaviruses are emerging pathogens that are carried by rodents and occasionally transmitted to man with lethal consequences. Our studies focus on Lassa fever virus due to its virulence for human beings. Lassa virus accounts for 300,000 annual infections and thousands deaths in West Africa. The sizeable disease burden and the possibility that LAS virus can be used as a biological warfare agent make a strong case for effective vaccine development. In contrast to the well-studied model of arenavirus pathogenesis in the mouse, the virulence of Lassa fever in man, guinea pigs and non-human primates is directly related to viremia, and less related to immune-mediated pathology. Guinea pigs are a potentially useful model for elucidating the pathogenesis of Lassa virus infection and for vaccine and treatment developments. A close relative of Lassa fever virus, Mopeia virus, is not lethal in guinea pigs and monkeys, and can protect them from Lassa virus challenge. To determine the genetic basis of Lassa virus virulence we made interspecies virus recombinants between Lassa (LAS) and Mopeia (MOP) viruses. We will test the hypothesis that the Lassa L RNA segment is associated with fatal acute disease in experimental animals and that the MOP/LAS reassortant virus consisting of the L RNA of Mopeia and the S RNA of Lassa will be avirulent and will confer effective protection from a lethal Lassa virus challenge. Our specific aims will be to: 1) compare the virulence of the reassortant MOP/LAS and LAS/MOP viruses with the virulence of the two parental, LAS and MOP viruses; 2) test the ability of the MOP/LAS reassortant to protect guinea pigs from lethal challenge with LAS virus. Virulence and protection will be measured in terms of survival, viremia, viral load in tissues, disturbances in clinical chemistry and hematology. Pro-inflammatory cyto/chemokines, TNF-alpha, IL-1beta, IL-6, and IL-8, will be monitored because clinical and experimental data showed involvement of these factors in LHF pathogenesis. Our long-range goal is to understand LAS virus pathogenesis and to develop effective treatments and vaccines.