MOP/LAS chimeric vaccine against Lassa fever

描述（由申请人提供）：沙粒病毒是一种新兴的病原体，由啮齿动物携带，偶尔传播给人类，造成致命后果。我们的研究重点是拉沙热病毒，因为它对人类的毒性。拉沙病毒每年在西非造成30万人感染，数千人死亡。巨大的疾病负担和LAS病毒可用作生物战剂的可能性，为开发有效的疫苗提供了强有力的理由。与沙病毒在小鼠中的发病机制的充分研究模型相反，拉沙热在人、豚鼠和非人灵长类动物中的毒力与病毒血症直接相关，而与免疫介导的病理关系较小。豚鼠是阐明拉沙病毒感染发病机制以及开发疫苗和治疗方法的潜在有用模型。拉沙热病毒的近亲莫皮亚病毒对豚鼠和猴子不致命，可保护它们免受拉沙病毒的攻击。为了确定拉沙病毒毒力的遗传基础，我们在拉沙病毒（LAS）和Mopeia病毒（MOP）之间进行了种间病毒重组。我们将在实验动物中验证拉沙L RNA片段与致命急性疾病相关的假设，以及由Mopeia的L RNA和拉沙的S RNA组成的MOP/LAS重组病毒将是无毒的，并将有效地保护人们免受致命拉沙病毒的攻击。我们的具体目标是：1)将重组的MOP/LAS和LAS/MOP病毒的毒力与两个亲本，LAS和MOP病毒的毒力进行比较；2)测试MOP/LAS重组物保护豚鼠免受LAS病毒致命攻击的能力。毒力和保护将根据存活、病毒血症、组织中的病毒载量、临床化学和血液学的紊乱来测量。将监测促炎细胞/趋化因子tnf - α、il -1 β、IL-6和IL-8，因为临床和实验数据显示这些因子参与LHF的发病机制。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.