Please wait a minute...

中国生物工程杂志

China Biotechnology
China Biotechnology  2020, Vol. 40 Issue (12): 25-30    DOI: 10.13523/j.cb.2009020
    
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
Download: HTML   PDF(5652KB) HTML
Export: BibTeX | EndNote (RIS)      

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 wordsSelf-amplifying mRNA vaccine      Alphavirus expression vectors      Replicon     
Received: 12 September 2020      Published: 14 January 2021
ZTFLH:  Q939Q812R373  
Corresponding Authors: Hui-yuan JING     E-mail: lhsjhy@126.com
Cite this article:

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

URL:

https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2009020     OR     https://manu60.magtech.com.cn/biotech/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
Table 1 Caparison between traditional non-replicating mRNA vaccines and self-amplifying mRNA vaccines
Fig.1 Schematic representation of different in vitro transcribed mRNA vaccines and genome structures (a) Traditional non-replicating mRNA vaccines (b) Self-amplifying mRNA vaccines (SAM) (c)Trans-amplifying mRNA vaccines (d) Nucleoside-modified trans-amplifying mRNA vaccines (e) SAM vaccine in combination with a SAM construct encoding GM-CSF
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]
Table 2 Self-amplifying mRNA vaccines against viral infectious disease
[1]   Mckay P F, Hu K, Blakney A K, et al. Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat Commun, 2020,11(1):3523.
doi: 10.1038/s41467-020-17409-9 pmid: 32647131
[2]   Erasmus J H, Khandhar A P, O’Connor M A, et al. An alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and t cell responses in mice and nonhuman primates. Sci Transl Med, 2020,12(555): eabc9396. DOI: 10.1126/scitranslmed.abc9396.
doi: 10.1126/scitranslmed.abc9396 pmid: 32690628
[3]   Maruggi G, Zhang C, Li J, et al. mRNA as a transformative technology for vaccine development to control infectious diseases. Mol Ther, 2019,27(4):757-772.
doi: 10.1016/j.ymthe.2019.01.020 pmid: 30803823
[4]   Carey B D, Bakovic A, Callahan V, et al. New world alphavirus protein interactomes from a therapeutic perspective. Antiviral Res, 2019,163:125-139.
doi: 10.1016/j.antiviral.2019.01.015 pmid: 30695702
[5]   Nadia R, Oney O G, Gilles Q, et al. Mutations on VEEV nsp1 relate RNA capping efficiency to ribavirin susceptibility. Antiviral Res, 2020,182:104883.
pmid: 32750467
[6]   Akhrymuk I, Lukash T, Frolov I, et al. Novel mutations in nsp2 abolish chikungunya virus-induced transcriptional shutoff and make the virus less cytopathic without affecting its replication rates. J Virol, 2019,93(4):e02062-18. DOI: 10.1128/JVI.02062-18.
doi: 10.1128/JVI.02062-18 pmid: 30487275
[7]   Abraham R, Hauer D, Mcpherson R L, et al. ADP-ribosyl-binding and hydrolase activities of the alphavirus nsp3 macrodomain are critical for initiation of virus replication. Proc Natl Acad Sci USA, 2018,115(44):E10457-E10466.
doi: 10.1073/pnas.1812130115 pmid: 30322911
[8]   Abraham R, Mcpherson R L, Dasovich M, et al: Both ADP-ribosyl-binding and hydrolase activities of the alphavirus nsp3 macrodomain affect neurovirulence in mice. mBio, 2020,11(1):e03253-19. DOI: 10.1128/mBio.03253-19.
doi: 10.1128/mBio.03253-19 pmid: 32047134
[9]   Skidmore A M, Adcock R S, Jonsson C B, et al. Benzamidine ml336 inhibits plus and minus strand RNA synthesis of venezuelan equine encephalitis virus without affecting host RNA production. Antiviral Res, 2020,174:104674.
doi: 10.1016/j.antiviral.2019.104674 pmid: 31816348
[10]   Zhang Y N, Chen C, Deng C L, et al. A novel rabies vaccine based on infectious propagating particles derived from hybrid VEEV-rabies replicon. EBioMedicine, 2020,56:102819.
doi: 10.1016/j.ebiom.2020.102819 pmid: 32512518
[11]   Tang J, Bi Z, Ding M, et al. Immunization with a suicidal DNA vaccine expressing the E glycoprotein protects ducklings against duck tembusu virus. Virol J, 2018,15(1):140.
doi: 10.1186/s12985-018-1053-0 pmid: 30217161
[12]   Beissert T, Perkovic M, Vogel A, et al. A trans-amplifying RNA vaccine strategy for induction of potent protective immunity. Mol Ther, 2020,28(1):119-128.
[13]   Brazzoli M, Magini D, Bonci A, et al. Induction of broad-based immunity and protective efficacy by self-amplifying mRNA vaccines encoding influenza virus hemagglutinin. J Virol, 2016,90(1):332-344.
doi: 10.1128/JVI.01786-15 pmid: 26468547
[14]   Hekele A, Bertholet S, Archer J, et al. Rapidly produced SAM vaccine against H7N9 influenza is immunogenic in mice. Emerg Microbes Infect, 2013,2(8):e52.
doi: 10.1038/emi.2013.54 pmid: 26038486
[15]   Chahal J S, Khan O F, Cooper C L, et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal ebola, H1N1 influenza, and toxoplasma gondii challenges with a single dose. Proc Natl Acad Sci USA, 2016,113(29):E4133-E4142.
doi: 10.1073/pnas.1600299113 pmid: 27382155
[16]   Fleeton M N, Chen M, Berglund P, et al. Self-replicative RNA vaccines elicit protection against influenza a virus, respiratory syncytial virus, and a tickborne encephalitis virus. J Infect Dis, 2001,183(9):1395-1398.
doi: 10.1086/319857 pmid: 11294672
[17]   Magini D, Giovani C, Mangiavacchi S, et al. Self-amplifying mRNA vaccines expressing multiple conserved influenza antigens confer protection against homologous and heterosubtypic viral challenge. PLoS One, 2016,11(8):e0161193.
doi: 10.1371/journal.pone.0161193 pmid: 27525409
[18]   Vogel A B, Lambert L, Kinnear E, et al. Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses. Mol Ther, 2018,26(2):446-455.
doi: 10.1016/j.ymthe.2017.11.017 pmid: 29275847
[19]   Manara C, Brazzoli M, Piccioli D, et al. Co-administration of gm-csf expressing RNA is a powerful tool to enhance potency of sam-based vaccines. Vaccine, 2019,37(30):4204-4213.
doi: 10.1016/j.vaccine.2019.04.028 pmid: 31227353
[20]   Zhang Y N, Li X D, Zhang Z R, et al. A mouse model for SARS-CoV-2 infection by exogenous delivery of hACE2 using alphavirus replicon particles. Cell Res, 2020. DOI: 10.1038/s41422-020-00405-5
doi: 10.1038/s41422-020-00405-5 pmid: 33159154
[21]   Chahal J S, Fang T, Woodham A W, et al. An RNA nanoparticle vaccine against zika virus elicits antibody and CD8 + T cell responses in a mouse model . Sci Rep, 2017,7(1):252.
pmid: 28325910
[22]   Erasmus J H, Khandhar A P, Guderian J, et al. A nanostructured lipid carrier for delivery of a replicating viral RNA provides single, low-dose protection against zika. Mol Ther, 2018,26(10):2507-2522.
doi: 10.1016/j.ymthe.2018.07.010 pmid: 30078765
[23]   Luisi K, Morabito K M, Burgomaster K E, et al. Development of a potent zika virus vaccine using self-amplifying messenger RNA. Sci Adv, 2020,6(32):eaba5068.
doi: 10.1126/sciadv.abb1724 pmid: 32821833
[24]   Saxena S, Sonwane A A, Dahiya S S, et al. Induction of immune responses and protection in mice against rabies using a self-replicating RNA vaccine encoding rabies virus glycoprotein. Vet Microbiol, 2009,136(1-2):36-44.
doi: 10.1016/j.vetmic.2008.10.030 pmid: 19081687
[25]   Lou G, Anderluzzi G, Schmidt S T, et al. Delivery of self-amplifying mRNA vaccines by cationic lipid nanoparticles: the impact of cationic lipid selection. J Control Release, 2020,325:370-379.
doi: 10.1016/j.jconrel.2020.06.027 pmid: 32619745
[26]   Stokes A, Pion J, Binazon O, et al. Nonclinical safety assessment of repeated administration and biodistribution of a novel rabies self-amplifying mRNA vaccine in rats. Regul Toxicol Pharmacol, 2020,113:104648.
doi: 10.1016/j.yrtph.2020.104648 pmid: 32240713
[27]   Ajbani S P, Velhal S M, Kadam R B, et al. Immunogenicity of semliki forest virus based self-amplifying RNA expressing indian HIV-1C genes in mice. Int J Biol Macromol, 2015,81:794-802.
doi: 10.1016/j.ijbiomac.2015.09.010 pmid: 26361864
[28]   Moyo N, Vogel A B, Buus S, et al. Efficient induction of T cells against conserved HIV-1 regions by mosaic vaccines delivered as self-amplifying mRNA. Mol Ther Methods Clin Dev, 2019,12:32-46.
doi: 10.1016/j.omtm.2018.10.010 pmid: 30547051
[29]   Brito L A, Chan M, Shaw C A, et al. A cationic nanoemulsion for the delivery of next-generation RNA vaccines. Mol Ther, 2014,22(12):2118-2129.
doi: 10.1038/mt.2014.133 pmid: 25027661
[30]   Brito L A, Kommareddy S, Maione D, et al. Self-amplifying mRNA vaccines. Adv Genet, 2015,89:179-233.
doi: 10.1016/bs.adgen.2014.10.005 pmid: 25620012
[31]   Samsa M M, Dupuy L C, Beard C W, et al. Self-amplifying RNA vaccines for venezuelan equine encephalitis virus induce robust protective immunogenicity in mice. Mol Ther, 2019,27(4):850-865.
doi: 10.1016/j.ymthe.2018.12.013 pmid: 30770173
No related articles found!