Rumyantsev Alexander A, Chanock Robert M, Murphy Brian R, Pletnev Alexander G
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MSC 8133, Bethesda, MD 20892-8133, USA.
Vaccine. 2006 Jan 12;24(2):133-43. doi: 10.1016/j.vaccine.2005.07.067. Epub 2005 Aug 9.
Three antigenic chimeric live attenuated tick-borne encephalitis virus (TBEV) vaccine candidates were compared for level of replication in murine and human neuroblastoma cells, for neurovirulence and neuroinvasiveness in mice, and for safety, immunogenicity and efficacy in rhesus monkeys. Two chimeric viruses were generated by replacing the membrane precursor and envelope protein genes of dengue type 4 virus (DEN4) with the corresponding genes of a Far Eastern TBEV, Sofjin strain, in the presence (TBEV/DEN4Delta30) or absence (TBEV/DEN4) of a 30 nucleotide deletion (Delta30) in the 3' noncoding region of the DEN4 part of the chimeric genome. A third chimeric TBEV vaccine candidate was based on the antigenically distant, but naturally attenuated Langat virus (LGT). Chimerization of LGT with DEN4 resulted in decreased neurovirulence and neuroinvasiveness in mice and highly restricted viremia in rhesus monkeys. Also, the LGT/DEN4 chimera was highly restricted in replication in both murine and human neuroblastoma cells. In contrast, TBEV/DEN4 and TBEV/DEN4Delta30 were neither attenuated for neurovirulence in the mice nor restricted in replication in the neuroblastoma cells. However, both were highly attenuated for neuroinvasiveness in mice. TBEV/DEN4 replicated to moderately high titer in rhesus monkeys (mean peak viremia=10(3.1)PFU/ml) indicating that the TBEV/DEN4 chimerization had only a modest, if any, attenuating effect in monkeys. However, the addition of the Delta30 mutation to TBEV/DEN4 greatly attenuated the chimeric virus for rhesus monkeys (mean peak viremia=10(0.7)PFU/ml) and induced a higher level of antibody against the TBEV than did LGT/DEN4. A single dose of either highly attenuated TBEV/DEN4Delta30 or LGT/DEN4 vaccine candidate or three doses of an inactivated TBEV vaccine were efficacious in monkeys against wild-type LGT challenge. These results indicate that both TBEV/DEN4Delta30 and LGT/DEN4 are safe and efficacious in rhesus monkeys and should be further evaluated as vaccine candidates for use in humans.
对三种抗原性嵌合的蜱传脑炎病毒（TBEV）减毒活疫苗候选株进行了比较，包括在鼠和人神经母细胞瘤细胞中的复制水平、在小鼠中的神经毒力和神经侵袭性，以及在恒河猴中的安全性、免疫原性和有效性。通过用远东TBEV Sofjin株的相应基因替换登革4型病毒（DEN4）的膜前体和包膜蛋白基因，构建了两种嵌合病毒，其中一种嵌合病毒（TBEV/DEN4Delta30）的嵌合基因组中DEN4部分的3'非编码区存在30个核苷酸的缺失（Delta30），另一种（TBEV/DEN4）则不存在该缺失。第三种嵌合TBEV疫苗候选株基于抗原性差异较大但自然减毒的Langat病毒（LGT）。LGT与DEN4嵌合后，小鼠的神经毒力和神经侵袭性降低，恒河猴的病毒血症受到高度限制。此外，LGT/DEN4嵌合体在鼠和人神经母细胞瘤细胞中的复制也受到高度限制。相比之下，TBEV/DEN4和TBEV/DEN4Delta30在小鼠中的神经毒力未减弱，在神经母细胞瘤细胞中的复制也未受限。然而，二者在小鼠中的神经侵袭性均显著减弱。TBEV/DEN4在恒河猴中的复制达到中等高水平（平均峰值病毒血症=10(3.1)PFU/ml），表明TBEV/DEN4嵌合对猴子的减毒作用甚微（如果有作用的话）。然而，在TBEV/DEN4中加入Delta30突变后，嵌合病毒对恒河猴的减毒作用大大增强（平均峰值病毒血症=10(0.7)PFU/ml），并且诱导产生的抗TBEV抗体水平高于LGT/DEN4。单剂量的高度减毒TBEV/DEN4Delta30或LGT/DEN4疫苗候选株或三剂量的灭活TBEV疫苗对猴子抵抗野生型LGT攻击均有效。这些结果表明，TBEV/DEN4Delta30和LGT/DEN4在恒河猴中均安全有效，应作为人类疫苗候选株进一步评估。
