Leitner W W, Ying H, Restifo N P
National Cancer Institute, National Institutes of Health, Building 10, Bethesda, MD 20892-1502, USA.
Vaccine. 1999 Dec 10;18(9-10):765-77. doi: 10.1016/s0264-410x(99)00271-6.
DNA vaccines were introduced less than a decade ago but have already been applied to a wide range of infectious and malignant diseases. Here we review the current understanding of the mechanisms underlying the activities of these new vaccines. We focus on recent strategies designed to enhance their function including the use of immunostimulatory (CpG) sequences, dendritic cells (DC), co-stimulatory molecules and cytokine- and chemokine-adjuvants. Although genetic vaccines have been significantly improved, they may not be sufficiently immunogenic for the therapeutic vaccination of patients with infectious diseases or cancer in clinical trials. One promising approach aimed at dramatically increasing the immunogenicity of genetic vaccines involves making them 'self-replicating'. This can be accomplished by using a gene encoding RNA replicase, a polyprotein derived from alphaviruses, such as Sindbis virus. Replicase-containing RNA vectors are significantly more immunogenic than conventional plasmids, immunizing mice at doses as low as 0.1 microg of nucleic acid injected once intramuscularly. Cells transfected with 'self-replicating' vectors briefly produce large amounts of antigen before undergoing apoptotic death. This death is a likely result of requisite double-stranded (ds) RNA intermediates, which also have been shown to super-activate DC. Thus, the enhanced immunogenicity of 'self-replicating' genetic vaccines may be a result of the production of pro-inflammatory dsRNA, which mimics an RNA-virus infection of host cells.
DNA疫苗问世还不到十年，但已被应用于多种传染病和恶性疾病。在此，我们综述了目前对这些新型疫苗作用机制的认识。我们重点关注了旨在增强其功能的近期策略，包括使用免疫刺激（CpG）序列、树突状细胞（DC）、共刺激分子以及细胞因子和趋化因子佐剂。尽管基因疫苗已有显著改进，但在临床试验中，它们对于传染病或癌症患者的治疗性疫苗接种而言，免疫原性可能仍不够强。一种旨在大幅提高基因疫苗免疫原性的有前景的方法是使其“自我复制”。这可以通过使用编码RNA复制酶的基因来实现，该复制酶是一种源自α病毒（如辛德毕斯病毒）的多聚蛋白。含复制酶的RNA载体比传统质粒的免疫原性显著更强，以低至0.1微克核酸的剂量单次肌肉注射就能使小鼠产生免疫反应。用“自我复制”载体转染的细胞在经历凋亡死亡之前会短暂产生大量抗原。这种死亡可能是必需的双链（ds）RNA中间体导致的结果，dsRNA也已被证明能超级激活树突状细胞。因此，“自我复制”基因疫苗免疫原性增强可能是由于促炎性dsRNA的产生，它模拟了宿主细胞的RNA病毒感染。
