New generation of efficient vaccines against encephalitogenic alphaviruses

描述（由申请方提供）：披膜病毒科甲病毒属包含许多广泛分布的重要人类和动物病原体。新世界甲病毒包括委内瑞拉（VEEV）、东部（EEEV）和西部马脑炎（WEEV）病毒，是美国严重的公共卫生威胁，可被生物恐怖分子应用。然而，迄今为止，既没有开发出有效的抗病毒药物，也没有开发出安全有效的疫苗来预防VEEV、EEEV或WEEV感染。现有的实验性疫苗要么疗效不佳，要么在人体内表现出非常强烈的不良反应。我们对甲病毒发病机制的分子机制的研究为开发针对致脑炎的新世界甲病毒的新型候选疫苗提供了独特的机会。在拟定研究中产生的候选疫苗将证明i）高度减毒的表型，这是基于它们不能干扰先天免疫应答的诱导; ii）由于大量冗余突变，减毒表型将是不可逆的; iii）设计的突变体将在体内引起流产感染，但它们将维持在Vero细胞中复制至高滴度的能力。iv）设计的病毒的基因组将包含额外的、广泛的修改，这使得这些病毒不能在蚊子细胞和载体中复制。因此，它们将被排除在自然循环之外。

DESCRIPTION (provided by applicant): The Alphavirus genus in the Togaviridae family contains a number of widely distributed important human and animal pathogens. The New World alphaviruses, which include Venezuelan (VEEV), eastern (EEEV) and western equine encephalitis (WEEV) viruses, represent a serious public health threat in the US and can be applied by bioterrorists. However, to date, neither effective antivirals nor safe and efficient vaccines have been developed for preventing VEEV, EEEV or WEEV infections. The existing experimental vaccines are either of poor efficacy or demonstrate very strong adverse reactions in humans. Our studies of the molecular mechanism of alphavirus pathogenesis provided a unique opportunity to develop a new type of vaccine candidates against encephalitogenic, New World alphaviruses. The generated in the proposed study vaccine candidates will demonstrate i) highly attenuated phenotype, which is based on their inability to interfere with the induction of the innate immune response; ii) the attenuated phenotype will be irreversible due to large number of redundant mutations; iii) the designed mutants will cause an abortive infection in vivo, but they will sustain the ability for replication to high titers in Vero cells. iv) The genomes of the designed viruses will contain additional, extensive modifications, which make these viruses incapable of replicating in mosquito cells and vectors. Thus, they will be excluded from the natural circulation.