Leitner Wolfgang W, Bergmann-Leitner Elke S, Hwang Leroy N, Restifo Nicholas P
Clinical Research Center, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Vaccine. 2006 Jun 12;24(24):5110-8. doi: 10.1016/j.vaccine.2006.04.059. Epub 2006 May 6.
The immunogenicity and efficacy of nucleic acid vaccines can be greatly enhanced when antigen production is under the control of an alphaviral replicase enzyme. However, replicase-mediated mRNA overproduction does not necessarily result in enhanced antigen level. Instead, the strong adaptive immune response of alphavirus replicon-based vectors is due to their production of double-stranded RNA (dsRNA) intermediates, which trigger innate immunity. Because viral infections are known to trigger innate immune responses that lead to the rapid production of Type I Interferons (IFNs), namely IFN-alpha and IFN-beta, we investigated the role of Type I IFNs in the enhanced immunogenicity of replicase-based DNA vaccines. In vitro, cells transfected with replicase-based plasmids produce significantly more Type I IFNs than cells transfected with a conventional DNA plasmid. In vivo, replicase-based DNA vaccines yield stronger humoral responses in the absence of Type I IFN signaling but the lack of this signaling pathway in IFN-alphabeta receptor-/- (knockout) mice abolishes T cell mediated efficacy against tumors of both conventional and alphavirus replicase-based DNA vaccines. Moreover, the co-delivery of an IFNalpha-encoding plasmid significantly improved the efficacy of a weakly immunogenic conventional plasmid. These results suggest a central role for Type I IFNs in the mechanism of replicase-based DNA vaccines and indicate that vaccines can be enhanced by enabling their capacity to triggering innate anti-viral defense pathways.
当抗原产生受甲病毒复制酶控制时，核酸疫苗的免疫原性和效力可得到极大增强。然而，复制酶介导的mRNA过量产生并不一定会导致抗原水平提高。相反，基于甲病毒复制子的载体产生强烈的适应性免疫反应是由于其产生双链RNA（dsRNA）中间体，从而触发先天免疫。由于已知病毒感染会触发导致I型干扰素（IFN）快速产生的先天免疫反应，即IFN-α和IFN-β，我们研究了I型干扰素在基于复制酶的DNA疫苗增强免疫原性中的作用。在体外，用基于复制酶的质粒转染的细胞比用传统DNA质粒转染的细胞产生显著更多的I型干扰素。在体内，基于复制酶的DNA疫苗在缺乏I型干扰素信号的情况下产生更强的体液反应，但IFN-αβ受体敲除小鼠中该信号通路的缺失消除了T细胞介导的对传统和基于甲病毒复制酶的DNA疫苗肿瘤的效力。此外，共递送编码IFN-α的质粒显著提高了弱免疫原性传统质粒的效力。这些结果表明I型干扰素在基于复制酶的DNA疫苗机制中起核心作用，并表明通过使其能够触发先天抗病毒防御途径可增强疫苗效果。
