PDF(Pubmed)
Abstract：
Self-amplifying RNAs (saRNAs) are versatile vaccine platforms that take advantage of a viral RNA-dependent RNA polymerase (RdRp) to amplify the messenger RNA (mRNA) of an antigen of interest encoded within the backbone of the viral genome once inside the target cell. In recent years, more saRNA vaccines have been clinically tested with the hope of reducing the vaccination dose compared to the conventional mRNA approach. The use of N1-methyl-pseudouridine (1mΨ), which enhances RNA stability and reduces the innate immune response triggered by RNAs, is among the improvements included in the current mRNA vaccines. In the present study, we evaluated the effects of this modified nucleoside on various saRNA platforms based on different viruses. The results showed that different stages of the replication process were affected depending on the backbone virus. For TNCL, an insect virus of the Alphanodavirus genus, replication was impaired by poor recognition of viral RNA by RdRp. In contrast, the translation step was severely abrogated in coxsackievirus B3 (CVB3), a member of the Picornaviridae family. Finally, the effects of 1mΨ on Semliki forest virus (SFV), were not detrimental in in vitro studies, but no advantages were observed when immunogenicity was tested in vivo.
摘要：
自扩增RNA(saRNA)是多功能疫苗平台,其利用病毒RNA依赖性RNA聚合酶(RdRp)来扩增一旦在靶细胞内在病毒基因组的骨架内编码的目标抗原的信使RNA(mRNA)。近年来,更多的saRNA疫苗已经进行了临床试验,希望与常规mRNA方法相比减少疫苗接种剂量.使用N1-甲基-假尿苷（1mp），增强RNA稳定性并减少由RNA引发的先天免疫反应，是当前mRNA疫苗中包括的改进之一。在本研究中,我们评估了这种修饰的核苷在基于不同病毒的各种saRNA平台上的作用。结果表明，复制过程的不同阶段受到骨架病毒的影响。对于TNCL，一种Alphanodavirus属的昆虫病毒，复制因RdRp对病毒RNA的识别力差而受损。相比之下,翻译步骤在柯萨奇病毒B3（CVB3）中被严重废除，Picornaviridae家族的成员。最后,1熔点对Semliki森林病毒（SFV）的影响，在体外研究中没有损害，但是在体内测试免疫原性时没有观察到优势。
