复制型mRNA技术在传染病疫苗研发中的应用  

Application of self-amplifying mRNA technology in the development of infectious disease vaccines

作　　者：李晓丹[1] 王鑫 张波[2] Xiaodan Li;Xin Wang;Bo Zhang(School of Medicine,Hunan Normal University,Changsha 410031,China;Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430207,China)

机构地区：[1]湖南师范大学医学院,长沙410031 [2]中国科学院武汉病毒研究所,武汉430207

出　　处：《科学通报》2024年第33期4889-4904,共16页Chinese Science Bulletin

基　　金：国家自然科学基金联合基金(U20A2014)资助。

摘　　要：mRNA疫苗是下一代疫苗的重要平台,其安全有效和研发周期短的特点在应对新发传染病和其他疾病治疗方面具有巨大优势.复制型mRNA(self-amplifying, saRNA)是从正链RNA病毒基因组衍生而来的具有自我复制能力的mRNA,能够以低剂量注射实现高水平的目的蛋白表达.基于saRNA的疫苗有潜力解决常规非复制型mRNA疫苗使用剂量大和重复接种的问题.近年来, saRNA合成、载体优化及递送等技术发展迅速,大大推进了saRNA疫苗的发展,目前有多种传染病saRNA疫苗正在研发中.本文介绍了saRNA疫苗的作用机制和递送方式,对近年来针对病毒性传染病的saRNA疫苗进行综述,总结了saRNA疫苗设计的一般策略和优化方法,讨论了saRNA疫苗研发面临的挑战,并展望了saRNA在传染病防治中的其他研究方向,以期为saRNA在传染病防治中的应用提供借鉴.The mRNA vaccine has become a promising platform for prevention and treatment of infectious diseases due to its advantages of high efficacy,low risk of genetic integration and rapid development cycle.The current mRNA technologies include three types of synthetic RNAs which are conventional linear mRNA,circular RNA and self-amplifying mRNA(saRNA).Both conventional linear mRNA and circular RNA are non-amplifying,and the protein expression levels depend on the amount of RNAs delivered into cells.Therefore,high mRNA doses and repetitive vaccination of the conventional mRNA vaccines are often required to induce adequate immune responses.saRNAs are derived from the genomes of positive-strand RNA viruses in which the coding sequences of viral structural proteins are replaced by a heterologous gene of interest(GOI).saRNAs carry the viral replicase genes and therefore maintain self-replicative activity in the host cells,leading to enhanced and lasting expression of the GOI.It has been reported that compared to the conventional mRNA vaccines,lower doses of saRNAs can provide similar expression levels of the antigens and stimulate equivalent or even more potent immune responses in vivo.Therefore,compared to conventional mRNA vaccines,the saRNA-based vaccines have potential to decrease the initial RNA dosage and immunization frequency,thereby minimizing the potential side effects associated with the delivery materials and also making the vaccination less costly.However,the development of saRNA vaccines faces greater challenges than conventional mRNA vaccines.Due to the large size of the genome,the synthesis and delivery of saRNA is more difficult than that of conventional mRNA.In addition,the self-replicating property of saRNAs also increases their innate immunogenicity,which may lead to degradation of saRNAs and interfere with the therapeutic outcome of GOI.In recent years,tremendous efforts have been put into the optimization of saRNA synthesis,vector design and delivery systems to overcome these issues,and the relevant ad

关 键 词：复制型mRNA 复制子 疫苗 mRNA递送 

分 类 号：R392[医药卫生—免疫学]