The epitope integration site for vaccine antigens determines virus control while maintaining efficacy in an engineered cancer vaccine.
The epitope integration site for vaccine antigens determines virus control while maintaining efficacy in an engineered cancer vaccine.
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疫苗抗原的表位整合位点决定了病毒控制，同时保持工程癌症疫苗的功效。
DOI：
10.1038/mt.2013.52
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Pease,LarryR
中科院分区：
文献类型：
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作者：
Pavelko,KevinD;Bell,MichaelP;Karyampudi,Lavakumar;Hansen,MichaelJ;Allen,KathleenS;Knutson,KeithL;Pease,LarryR
微小核糖核酸病毒已被开发为基因传递和疫苗接种的潜在疗法。使用它们的一个缺点是重组和病毒持续存在的可能性。因此，所使用的工程策略必须考虑到病毒逃逸的可能性。我们已经开发出泰勒氏小鼠脑脊髓炎病毒(TMEV)作为一种潜在的疫苗载体，用于免疫治疗。这项研究表明，在TMEV Leader蛋白中的一个独特位置插入疫苗表位可以显著提高I型干扰素(IFN)对感染的反应，并促进病毒的快速清除。这种活病毒疫苗保持了其对模型抗原和弱免疫原性肿瘤抗原Her2/neu的抗原特异性CD8+T细胞反应的能力。此外，表位整合位点并不影响该疫苗作为癌症免疫疗法治疗黑色素瘤和乳腺癌模型的有效性，这一点从移植这些肿瘤的动物身上延缓肿瘤生长和提高存活率来证明。这些发现表明，保持有限复制能力的减毒病毒可以有效地动员CD8+细胞免疫，这对临床上用于免疫治疗的微小核糖核酸病毒载体的设计将是重要的。
Picornaviruses have been developed as potential therapies for gene delivery and vaccination. One drawback to their use is the potential for recombination and viral persistence. Therefore, the engineering strategies used must take into account the possibility for virus escape. We have developed Theiler's murine encephalomyelitis virus (TMEV) as a potential vaccine vector for use in immunotherapy. This study shows that insertion of a vaccine epitope at a unique site within the TMEV leader protein can dramatically increase the type I interferon (IFN) response to infection and promote rapid viral clearance. This live virus vaccine maintains its ability to drive antigen-specific CD8+T-cell responses to a model antigen as well as to the weakly immunogenic tumor antigen Her2/neu. Furthermore, the epitope integration site does not affect the efficacy of this vaccine as cancer immunotherapy for treating models of melanoma and breast cancer as demonstrated by delayed tumor outgrowth and increased survival in animals implanted with these tumors. These findings show that an attenuated virus retaining limited ability to replicate nonetheless can effectively mobilize CD8+cellular immunity and will be important for the design of picornavirus vectors used as immunotherapy in clinical settings.