Department of Microbiology and Immunology, Bluemle Life Science Building, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Microbiology and Immunology, Bluemle Life Science Building, Thomas Jefferson University, Philadelphia, PA 19107, USA; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga 4710-057, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães 4806-909, Portugal.
Mol Ther. 2021 Sep 1;29(9):2769-2781. doi: 10.1016/j.ymthe.2021.05.011. Epub 2021 May 14.
It is well established that memory CD8 T cells protect susceptible strains of mice from mousepox, a lethal viral disease caused by ectromelia virus (ECTV), the murine counterpart to human variola virus. While mRNA vaccines induce protective antibody (Ab) responses, it is unknown whether they also induce protective memory CD8 T cells. We now show that immunization with different doses of unmodified or N(1)-methylpseudouridine-modified mRNA (modified mRNA) in lipid nanoparticles (LNP) encoding the ECTV gene EVM158 induced similarly strong CD8 T cell responses to the epitope TSYKFESV, albeit unmodified mRNA-LNP had adverse effects at the inoculation site. A single immunization with 10 μg modified mRNA-LNP protected most susceptible mice from mousepox, and booster vaccination increased the memory CD8 T cell pool, providing full protection. Moreover, modified mRNA-LNP encoding TSYKFESV appended to green fluorescent protein (GFP) protected against wild-type ECTV infection while lymphocytic choriomeningitis virus glycoprotein (GP) modified mRNA-LNP protected against ECTV expressing GP epitopes. Thus, modified mRNA-LNP can be used to create protective CD8 T cell-based vaccines against viral infections.
已有充分证据表明，记忆性 CD8 T 细胞可保护易感染的小鼠免受小鼠痘的侵害，小鼠痘是由细小病毒（ECTV）引起的致命病毒性疾病，细小病毒是人类天花病毒的啮齿动物对应物。虽然 mRNA 疫苗可诱导保护性抗体（Ab）应答，但尚不清楚它们是否也可诱导保护性记忆性 CD8 T 细胞。我们现在表明，用不同剂量的未经修饰或 N(1)-甲基假尿嘧啶修饰的 mRNA（修饰的 mRNA）在脂质纳米颗粒（LNP）中编码 ECTV 基因 EVM158 进行免疫接种可诱导针对表位 TSYKFESV 的相似强烈的 CD8 T 细胞反应，尽管未经修饰的 mRNA-LNP 在接种部位有不良影响。单次接种 10 μg 修饰的 mRNA-LNP 可使大多数易感染的小鼠免受小鼠痘的侵害，而加强疫苗接种可增加记忆性 CD8 T 细胞池，提供完全保护。此外，修饰的 mRNA-LNP 编码 TSYKFESV 附加绿色荧光蛋白（GFP）可预防野生型 ECTV 感染，而淋巴细胞性脉络丛脑膜炎病毒糖蛋白（GP）修饰的 mRNA-LNP 可预防表达 GP 表位的 ECTV。因此，修饰的 mRNA-LNP 可用于开发针对病毒感染的基于保护性 CD8 T 细胞的疫苗。
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