Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Vector Borne Zoonotic Dis. 2011 Jun;11(6):665-74. doi: 10.1089/vbz.2010.0179. Epub 2010 Dec 13.
In an effort to derive an efficacious live attenuated vaccine against tick-borne encephalitis, we generated a chimeric virus bearing the structural protein genes of a Far Eastern subtype of tick-borne encephalitis virus (TBEV) on the genetic background of recombinant dengue 4 (DEN4) virus. Introduction of attenuating mutations into the TBEV envelope protein gene, as well as the DEN4 NS5 protein gene and 3' noncoding region in the chimeric genome, results in decreased neurovirulence and neuroinvasiveness in mice, and restricted replication in mouse brain. Since TBEV and DEN4 viruses are transmitted in nature by ticks and mosquitoes, respectively, it was of interest to investigate the infectivity of the chimeric virus for both arthropod vectors. Therefore, parental and chimeric viruses were tested for growth in mosquito and tick cells and for oral infection in vivo. Although all chimeric viruses demonstrated moderate levels of replication in C6/36 mosquito cells, they were unable to replicate in ISE6 tick cells. Further, the chimeric viruses were unable to infect or replicate in Aedes aegypti mosquitoes and Ixodes scapularis tick larvae. The poor infectivity for both potential vectors reinforces the safety of chimeric virus-based vaccine candidates for the environment and for use in humans.
为了开发一种针对蜱传脑炎的有效减毒活疫苗，我们在重组登革热 4 型（DEN4）病毒的遗传背景下，生成了一种嵌合病毒，该病毒携带蜱传脑炎病毒（TBEV）远东型的结构蛋白基因。在嵌合基因组中，TBEV 包膜蛋白基因、DEN4 NS5 蛋白基因和 3'非编码区的引入导致病毒在小鼠中的神经毒力和神经侵袭性降低，并且在小鼠脑中的复制受到限制。由于 TBEV 和 DEN4 病毒在自然界中分别由蜱和蚊子传播，因此研究嵌合病毒对这两种节肢动物载体的感染力很有意思。因此，对亲本病毒和嵌合病毒在蚊子细胞和蜱细胞中的生长情况以及体内口服感染情况进行了测试。尽管所有嵌合病毒在 C6/36 蚊子细胞中均显示出中等水平的复制能力，但它们无法在 ISE6 蜱细胞中复制。此外，嵌合病毒无法感染或在埃及伊蚊和印鼠客蚤幼虫中复制。对于两种潜在载体的低感染力，进一步增强了基于嵌合病毒的候选疫苗在环境中的安全性，以及在人类中的使用安全性。
