Paessler Slobodan, Fayzulin Rafik Z, Anishchenko Michael, Greene Ivorlyne P, Weaver Scott C, Frolov Ilya
Center for Biodefense and Emerging Infectious Diseases, Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609, USA.
J Virol. 2003 Sep;77(17):9278-86. doi: 10.1128/jvi.77.17.9278-9286.2003.
Venezuelan equine encephalitis virus (VEEV) is an important, naturally emerging zoonotic virus. VEEV was a significant human and equine pathogen for much of the past century, and recent outbreaks in Venezuela and Colombia (1995), with about 100,000 human cases, indicate that this virus still poses a serious public health threat. The live attenuated TC-83 vaccine strain of VEEV was developed in the 1960s using a traditional approach of serial passaging in tissue culture of the virulent Trinidad donkey (TrD) strain. This vaccine presents several problems, including adverse, sometimes severe reactions in many human vaccinees. The TC-83 strain also retains residual murine virulence and is lethal for suckling mice after intracerebral (i.c.) or subcutaneous (s.c.) inoculation. To overcome these negative effects, we developed a recombinant, chimeric Sindbis/VEE virus (SIN-83) that is more highly attenuated. The genome of this virus encoded the replicative enzymes and the cis-acting RNA elements derived from Sindbis virus (SINV), one of the least human-pathogenic alphaviruses. The structural proteins were derived from VEEV TC-83. The SIN-83 virus, which contained an additional adaptive mutation in the nsP2 gene, replicated efficiently in common cell lines and did not cause detectable disease in adult or suckling mice after either i.c. or s.c. inoculation. However, SIN-83-vaccinated mice were efficiently protected against challenge with pathogenic strains of VEEV. Our findings suggest that the use of the SINV genome as a vector for expression of structural proteins derived from more pathogenic, encephalitic alphaviruses is a promising strategy for alphavirus vaccine development.
委内瑞拉马脑炎病毒（VEEV）是一种重要的、自然出现的人畜共患病毒。在过去的大部分时间里，VEEV都是一种重要的人类和马匹病原体，近期在委内瑞拉和哥伦比亚爆发的疫情（1995年）出现了约10万例人类病例，这表明该病毒仍然构成严重的公共卫生威胁。VEEV的减毒活疫苗株TC - 83是在20世纪60年代使用强毒株特立尼达驴（TrD）株在组织培养中连续传代的传统方法研制而成的。这种疫苗存在几个问题，包括许多人类接种者出现不良的、有时甚至是严重的反应。TC - 83株还保留有残余的鼠毒力，脑内（i.c.）或皮下（s.c.）接种后对乳鼠具有致死性。为克服这些负面影响，我们研制了一种重组嵌合辛德毕斯/委内瑞拉马脑炎病毒（SIN - 83），其减毒程度更高。该病毒的基因组编码复制酶和顺式作用RNA元件，这些元件源自辛德毕斯病毒（SINV），SINV是致病性最低的甲病毒之一。其结构蛋白源自VEEV TC - 83。SIN - 83病毒在nsP2基因中含有一个额外的适应性突变，能在常见细胞系中高效复制，脑内或皮下接种后在成年或乳鼠中均未引发可检测到的疾病。然而，接种SIN - 83的小鼠能有效抵御致病性VEEV毒株的攻击。我们的研究结果表明，将SINV基因组用作表达源自致病性更强的脑炎甲病毒的结构蛋白的载体，是甲病毒疫苗研发的一种有前景的策略。
