MOP/LAS chimeric vaccine against Lassa fever

抗拉沙热 MOP/LAS 嵌合疫苗

• 批准号: 6985337
• 负责人: Igor S. Lukashevich
• 金额: $ 38.29万
• 依托单位: UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985337
• 关键词: Arenaviridae; Lassa virus; biotechnology; clinical chemistry; guinea pigs; hematology; interleukin 1; interleukin 6; interleukin 8; recombinant virus; tumor necrosis factor alpha; vaccine development; viral vaccines; virulence; virus RNA; virus load

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.

描述（由申请人提供）：沙粒病毒是由啮齿动物携带的新出现的病原体，有时会传播给人类并造成致命后果。我们的研究重点是拉沙热病毒，因为它对人类具有毒力。拉沙病毒在西非每年造成 30 万人感染和数千人死亡。巨大的疾病负担以及 LAS 病毒可用作生物战剂的可能性为有效开发疫苗提供了强有力的理由。 与小鼠中经过充分研究的沙粒病毒发病机制模型相反，拉沙热对人、豚鼠和非人灵长类动物的毒力与病毒血症直接相关，与免疫介导的病理学关系不大。 豚鼠是阐明拉沙病毒感染发病机制以及疫苗和治疗开发的潜在有用模型。 拉沙热病毒的近亲莫佩亚病毒对豚鼠和猴子并不致命，可以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) 和莫皮亚 (MOP) 病毒之间进行了种间病毒重组。我们将测试以下假设：拉沙病毒 L RNA 片段与实验动物的致命急性疾病相关，并且由 Mopeia 的 L RNA 和拉沙病毒的 S RNA 组成的 MOP/LAS 重配病毒将是无毒的，并将提供有效的保护，免受致命的拉沙病毒的攻击。我们的具体目标是： 1) 将重配 MOP/LAS 和 LAS/MOP 病毒的毒力与两种亲本病毒 LAS 和 MOP 病毒的毒力进行比较； 2)测试MOP/LAS重配体保护豚鼠免受LAS病毒致命攻击的能力。 毒力和保护作用将根据存活率、病毒血症、组织中的病毒载量、临床化学和血液学的紊乱来衡量。将监测促炎细胞/趋化因子、TNF-α、IL-1β、IL-6 和 IL-8，因为临床和实验数据显示这些因素参与 LHF 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。