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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2020, Vol. 40 Issue (12): 25-30    DOI: 10.13523/j.cb.2009020
新型冠状病毒检测与治疗     
体外转录的自我复制型mRNA疫苗研究进展*
井汇源1,**(),段二珍2,董望1
1河南牧业经济学院 郑州 450046
2河南工业大学生物工程学院 郑州 450001
In Vitro Transcribed Self-amplifying mRNA Vaccines
JING Hui-yuan1,**(),DUAN Er-zhen2,DONG Wang1
1 Henan University of Animal Husbandry and Economy, Zhengzhou 450046, China
2 College of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
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摘要：

自我复制型mRNA是一种灵活的疫苗平台,该平台的开发基于甲病毒表达载体,其中复制必需基因得以完整保留,而结构蛋白基因则被来自病原的抗原基因替换。由于避免了病原培养、毒力返强和现存免疫的干扰,使其成为疫苗快速设计的理想平台。大量研究数据显示,此类疫苗可应用在人、小鼠、兔、猪、禽甚至鱼类体内诱导体液免疫和细胞免疫。过去,自我复制mRNA疫苗的研究采用重组单载体的模式,基因组骨架来源于辛德毕斯病毒、塞姆利基森林病毒和委内瑞拉马脑炎病毒。现在,反式复制型RNA和核酸修饰的反式复制型RNA作为下一代技术平台被寄予厚望。对基于甲病毒表达载体的mRNA疫苗技术的研究进展进行概述,重点介绍针对以流感病毒、新型冠状病毒和寨卡病毒等为代表的自我复制型mRNA疫苗研究现状,并探讨了该技术平台的未来发展方向。
关键词： 自我复制型mRNA疫苗;  甲病毒表达载体;  复制子    
Abstract:

Self-amplifying mRNA vaccine is a versatile vaccine platform developed from alphavirus expression vector in which the viral replication genes are intact but those viral structural genes are replaced with antigen genes derived from pathogens. These vaccines have emerged as ideal modalities for rapid vaccine design, avoiding the problem of pathogen culture, reversion to pathogenicity and pre-existing immunity. Numerous studies demonstrated that these vaccines could be employed to induce humoral and cellular immune responses in human, mice, rabbits, pigs, avian and even fish. During the past years, focus has been on the use of recombinant single vectored self-replicating mRNA derived from the genome backbone of Sindbis virus, Semliki forest virus, and Venezuelan equine encephalitis virus. Now trans-amplifying RNA and nucleotide modified trans-amplifying RNA vaccines have come into focus as promising next-generation technology platforms for vaccine development. An overview of recent advance in self-replicating RNA vaccines developed from alphavirus expression vectors was presented, with an emphasis on current state of SAM vaccine approaches against emerging infectious diseases, such as influenza A virus, SARS-CoV-2, and ZIKA virus, and provide perspectives on the future of this technology platform.
Key words: Self-amplifying mRNA vaccine    Alphavirus expression vectors    Replicon
收稿日期: 2020-09-12 出版日期: 2021-01-14
ZTFLH:  Q939Q812R373  
基金资助: * 国家自然科学基金(32002265);河南省自然科学基金资助项目(202300410187)
通讯作者: 井汇源     E-mail: lhsjhy@126.com
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井汇源
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引用本文:

井汇源,段二珍,董望. 体外转录的自我复制型mRNA疫苗研究进展*[J]. 中国生物工程杂志, 2020, 40(12): 25-30.

JING Hui-yuan,DUAN Er-zhen,DONG Wang. In Vitro Transcribed Self-amplifying mRNA Vaccines. China Biotechnology, 2020, 40(12): 25-30.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2009020    或    https://manu60.magtech.com.cn/biotech/CN/Y2020/V40/I12/25

传统mRNA疫苗(nrRNA) 自我复制型mRNA疫苗(saRNA、SAM)
优点 RNA长度短
可进行核酸修饰		 天然具备佐剂效应
注射剂量低,抗原表达量高,持续期长
缺点 注射剂量高,抗原表达量低
抗原表达低持续期短		 过度激活炎症反应风险
甲病毒非结构蛋白干扰细胞正常信号转导
共同点 不同抗原,疫苗生产和纯化工艺相同,适用于大规模工业化生产,成本低
无需培养细胞或鸡胚,无细胞和血清等成分污染
在细胞质发挥作用,无基因组整合风险,无致癌风险
无毒力反强风险,不产生子代病毒
不受母源抗体等体内现存抗体干扰,激活细胞免疫和体液免疫
免疫细胞激活晚于亚单位疫苗和减毒活疫苗
易降解,需低温保存,需合适的递送系统提升免疫效果
表1  传统mRNA疫苗和自我复制型mRNA疫苗的对比
图1  基于体外转录技术的mRNA疫苗的种类和基因组结构示意图
病毒 递送载体* 抗原 实验动物 文献
流感病毒 CNE、PEI、LNP、MDNP HA、NP、M1 小鼠、雪貂 [12-19]
2019新型冠状病毒 LNP S 小鼠、非人灵长类 [1-2]
寨卡病毒 CNE、MDNP prM、E、Capsid 小鼠、豚鼠、非人灵长类 [21-23]
狂犬病病毒 CNE、LNP G 小鼠 [24-26]
人免疫缺陷病病毒 CNE、PEI gag、env、polRT、gp160、
gp140、consvX		 小鼠、兔、非人灵长类 [27-29]
呼吸道合胞病毒 CNE、LNP F、G 小鼠、兔、非人灵长类 [16,29]
人巨细胞病毒 CNE、LNP gB、pp65、gH/gL 小鼠、兔、非人灵长类 [29-30]
埃博拉病毒 MDNP GP 小鼠 [15]
委内瑞拉马脑炎病毒 CNE E1、E2 小鼠 [31]
表2  针对病毒性传染病的自我复制型mRNA疫苗
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