Recombinant Sindbis/Venezuelan equine encephalitis virus is highly attenuated and immunogenic
Recombinant Sindbis/Venezuelan equine encephalitis virus is highly attenuated and immunogenic
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DOI：
10.1128/jvi.77.17.9278-9286.2003
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发表时间：
2003-09-01
影响因子：
5.4
通讯作者：
Frolov, I
中科院分区：
文献类型：
--
作者：
Paessler, S;Fayzulin, RZ;Frolov, I
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。VEEV在过去世纪的大部分时间里是一种重要的人类和马病原体，最近在委内瑞拉和哥伦比亚（1995年）爆发，约有100，000例人类病例，表明这种病毒仍然构成严重的公共卫生威胁。VEEV的TC-83减毒活疫苗株是在20世纪60年代使用在组织培养中对特立尼达驴（TrD）毒株进行连续传代的传统方法开发的。这种疫苗存在几个问题，包括在许多人类接种者中的不良反应，有时是严重的反应。TC-83菌株还保留了残余的鼠毒力，并且在脑内（i.c.）或皮下（s.c.）接种。为了克服这些负面影响，我们开发了一种重组的嵌合辛德毕斯/VEE病毒（SIN-83），其减毒程度更高。该病毒的基因组编码来自辛德毕斯病毒（SINV）的复制酶和顺式作用RNA元件，辛德毕斯病毒是对人类致病性最低的甲病毒之一。结构蛋白来源于VEEV TC-83。SIN-83病毒在nsP 2基因中含有额外的适应性突变，在普通细胞系中有效复制，并且在i.c.或s.c.接种。然而，SIN-83免疫的小鼠有效地保护免受VEEV致病株的攻击。我们的研究结果表明，使用SINV基因组作为载体表达来自致病性更强的脑炎甲病毒的结构蛋白是甲病毒疫苗开发的一种有前途的策略。
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.