MOP/LAS chimeric vaccine against Lassa fever

抗拉沙热 MOP/LAS 嵌合疫苗

• 批准号: 6829668
• 负责人: Igor S. Lukashevich
• 金额: $ 38.14万
• 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/6829668
• 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（由申请方提供）：沙粒病毒是一种由啮齿动物携带的新出现的病原体，偶尔会传播给人类并造成致命后果。由于拉沙热病毒对人类的毒性，我们的研究重点放在拉沙热病毒上。在西非，拉沙病毒每年造成30万人感染，数千人死亡。相当大的疾病负担和LAS病毒可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。 与沙粒病毒在小鼠中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，与免疫介导的病理学相关性较小。 豚鼠是阐明拉沙病毒感染的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不致命，可以保护它们免受拉沙热病毒的攻击。为了确定拉沙病毒毒力的遗传基础，我们在拉沙（LAS）和莫佩亚（MOP）病毒之间进行了种间病毒重组。我们将检验以下假设：拉沙L RNA片段与实验动物的致命性急性疾病相关，并且由Mopeia的L RNA和拉沙的S RNA组成的MOP/LAS抵抗病毒将是无毒的，并且将赋予有效的保护以免受致命的拉沙病毒攻击。我们的具体目标是：1）比较免疫原MOP/LAS和LAS/MOP病毒与两种亲本LAS和MOP病毒的毒力; 2）检测MOP/LAS免疫原保护豚鼠免受LAS病毒致死性攻击的能力。 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。