Encke J, Radunz W, Eisenbach C, Geib J, Gehrke S, Pfaff E, Stremmel W
University of Heidelberg, Heidelberg, Germany.
Eur J Clin Invest. 2007 May;37(5):396-406. doi: 10.1111/j.1365-2362.2007.01802.x.
Unquestionably viral diversity and genetic heterogeneity in hepatitis C virus (HCV) infection and other viral diseases play an essential role in viral immune escape and the development of chronicity. Despite this knowledge most vaccine approaches against HCV have excluded this important issue. Moreover the feasibility of developing an effective HCV vaccine has been questioned, mainly because prophylactic immunity against HCV cannot be achieved in chimpanzees by either vaccination or previous HCV infection, and reinfection in men has been reported, most likely due to genetic shift and immune escape. To analyse and characterize a new technique of a 'multigenotype'- and/or 'library'-vaccine, we established an envelope 1 (E1) plasmid vaccine against HCV and characterized humoral and cellular immune responses after vaccination in a mouse model.
Normally genetic information of one or two target proteins is cloned into a DNA-vaccine. In our approach we cloned a defined number of different genotypes and subtypes (defined vaccine, DV) or the genetic information from 20 patients (undefined) into a plasmid (library vaccine, LV).
As expected, immunized animals showed both stronger humoral (ELISA) and cellular (T-cell proliferation, ELISPOT) immune responses against genotype 1, since the stimulating antigen was genotype 1 derived. However, not all genotype 1 immunized animals recognized this viral antigen leading to the assumption that some epitopes lost their immunogenicity through a change in the amino acid sequence. Interestingly, some of the genotype 4 and 5 immunized mice sera were able to react against E1 protein.
Most of the assays showed immune reactivity against the DV or LV vaccine demonstrating the cross-reactive potential of such a vaccination approach. This cloning and immunization strategy based on the viral heterogeneity of the virus has in our view major implications for HCV, a virus with a broad viral genetic diversity, and may become in the future in the context of DNA- or viral-based vaccination strategies a possibility to overcome viral immune escape both in the prophylactic or therapeutic setting.
毫无疑问，丙型肝炎病毒（HCV）感染及其他病毒性疾病中的病毒多样性和基因异质性在病毒免疫逃逸和慢性化发展中起着至关重要的作用。尽管了解这一点，但大多数针对HCV的疫苗研发方法都忽略了这个重要问题。此外，开发一种有效的HCV疫苗的可行性受到质疑，主要是因为无论是通过接种疫苗还是先前的HCV感染，都无法在黑猩猩中实现针对HCV的预防性免疫，并且有报道称人类会再次感染，这很可能是由于基因转移和免疫逃逸。为了分析和表征一种“多基因型”和/或“文库”疫苗的新技术，我们构建了一种针对HCV的包膜1（E1）质粒疫苗，并在小鼠模型中接种疫苗后表征了体液免疫和细胞免疫反应。
通常，将一种或两种靶蛋白的遗传信息克隆到DNA疫苗中。在我们的方法中，我们将一定数量的不同基因型和亚型（定义疫苗，DV）或来自20名患者的遗传信息（未定义）克隆到一个质粒中（文库疫苗，LV）。
正如预期的那样，免疫动物对基因型1表现出更强的体液免疫（ELISA）和细胞免疫（T细胞增殖，ELISPOT）反应，因为刺激抗原源自基因型1。然而，并非所有接种基因型1的动物都能识别这种病毒抗原，这导致推测一些表位通过氨基酸序列的变化失去了免疫原性。有趣的是，一些接种基因型4和5的小鼠血清能够与E1蛋白发生反应。
大多数检测显示针对DV或LV疫苗具有免疫反应性，证明了这种疫苗接种方法的交叉反应潜力。我们认为，基于病毒基因异质性的这种克隆和免疫策略对HCV具有重要意义，HCV是一种具有广泛病毒基因多样性的病毒，并且在未来基于DNA或病毒的疫苗接种策略背景下，有可能在预防或治疗环境中克服病毒免疫逃逸。
