Zika Virus Attenuation by Codon Pair Deoptimization Induces Sterilizing Immunity in Mouse Models

doi:10.1128/JVI.00701-18

	Zika Virus Attenuation by Codon Pair Deoptimization Induces Sterilizing Immunity in Mouse Models
	Li, Penghui 2,3; Ke, Xianliang 2; Wang, Ting 1,2; Tan, Zhongyuan 2; Luo, Dan 2; Miao, Yuanjiu 2; Sun, Jianhong 2; Zhang, Yuan 2; Liu, Yan 2; Hu, Qinxue 4
刊名	JOURNAL OF VIROLOGY
	2018-09-01
卷号	92 期号:17 页码:16
关键词	codon pair bias E protein NS1 protein Zika virus deoptimization vaccines
ISSN号	0022-538X
DOI	10.1128/JVI.00701-18
英文摘要	Zika virus (ZIKV) infection during the large epidemics in the Americas is related to congenital abnormities or fetal demise. To date, there is no vaccine, antiviral drug, or other modality available to prevent or treat Zika virus infection. Here we designed novel live attenuated ZIKV vaccine candidates using a codon pair deoptimization strategy. Three codon pair-deoptimized ZIKVs (Min E, Min NS1, and Min E + NS1) were de novo synthesized and recovered by reverse genetics and contained large amounts of underrepresented codon pairs in the E gene and/or NS1 gene. The amino acid sequence was 100% unchanged. The codon pair-deoptimized variants had decreased replication fitness in Vero cells (Min NS1 >> Min E > Min E + NS1), replicated more efficiently in insect cells than in mammalian cells, and demonstrated diminished virulence in a mouse model. In particular, Min E = NS1, the most restrictive variant, induced sterilizing immunity with a robust neutralizing antibody titer, and a single immunization achieved complete protection against lethal challenge and vertical ZIKV transmission during pregnancy. More importantly, due to the numerous synonymous substitutions in the codon pair-deoptimized strains, reversion to wild-type virulence through gradual nucleotide sequence mutations is unlikely. Our results collectively demonstrate that ZIKV can be effectively attenuated by codon pair deoptimization, highlighting the potential of Min E + NS1 as a safe vaccine candidate to prevent ZIKV infections. IMPORTANCE Due to unprecedented epidemics of Zika virus (ZIKV) across the Americas and the unexpected clinical symptoms, including Guillain-Barre syndrome, microcephaly, and other birth defects in humans, there is an urgent need for ZIKV vaccine development. Here we provided the first attenuated versions of ZIKV with two important genes (E and/or NS1) that were subjected to codon pair deoptimization. Compared to parental ZIKV, the codon pair-deoptimized ZIKVs were mammal attenuated and preferred insect to mammalian cells. Min E + NS1, the most restrictive variant, induced sterilizing immunity with a robust neutralizing antibody titer and achieved complete protection against lethal challenge and vertical virus transmission during pregnancy. More importantly, the massive synonymous mutational approach made it impossible for the variant to revert to wild-type virulence. Our results have proven the feasibility of codon pair deoptimization as a strategy to develop live attenuated vaccine candidates against flaviviruses such as ZIKV, Japanese encephalitis virus, and West Nile virus.
资助项目	National Key R&D Program of China[2016YFD0500406] ; National Natural Science Foundation of China (NSFC)[81471953] ; Youth Innovation Promotion Association of CAS[2016302]
WOS关键词	INFLUENZA-VIRUS ; DINUCLEOTIDE BIAS ; CAPSID REGION ; VACCINE ; GENOME ; RNA ; PROTEIN ; PROTECTION ; REDUCTION ; CELLS
WOS研究方向	Virology
语种	英语
出版者	AMER SOC MICROBIOLOGY
WOS记录号	WOS:000443012300019
资助机构	National Key R&D Program of China ; National Key R&D Program of China ; National Natural Science Foundation of China (NSFC) ; National Natural Science Foundation of China (NSFC) ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; National Key R&D Program of China ; National Key R&D Program of China ; National Natural Science Foundation of China (NSFC) ; National Natural Science Foundation of China (NSFC) ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; National Key R&D Program of China ; National Key R&D Program of China ; National Natural Science Foundation of China (NSFC) ; National Natural Science Foundation of China (NSFC) ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; National Key R&D Program of China ; National Key R&D Program of China ; National Natural Science Foundation of China (NSFC) ; National Natural Science Foundation of China (NSFC) ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS
内容类型	期刊论文
源URL	[http://ir.wipm.ac.cn/handle/112942/13072]
专题	中国科学院武汉物理与数学研究所
通讯作者	Wang, Hanzhong; Zheng, Zhenhua
作者单位	1.Chinese Acad Sci, Key Lab Magnet Resonance Biol Syst, State Key Lab Magnet Resonance & Atom & Mol Phys, Wuhan Ctr Magnet Resonance,Wuhan Inst Phys & Math, Wuhan, Hubei, Peoples R China 2.Chinese Acad Sci, Wuhan Inst Virol, Ctr Emerging Infect Dis, CAS Key Lab Special Pathogens & Biosafety, Wuhan, Hubei, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.Chinese Acad Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan, Hubei, Peoples R China
推荐引用方式 GB/T 7714	Li, Penghui,Ke, Xianliang,Wang, Ting,et al. Zika Virus Attenuation by Codon Pair Deoptimization Induces Sterilizing Immunity in Mouse Models[J]. JOURNAL OF VIROLOGY,2018,92(17):16.
APA	Li, Penghui.,Ke, Xianliang.,Wang, Ting.,Tan, Zhongyuan.,Luo, Dan.,...&Zheng, Zhenhua.(2018).Zika Virus Attenuation by Codon Pair Deoptimization Induces Sterilizing Immunity in Mouse Models.JOURNAL OF VIROLOGY,92(17),16.
MLA	Li, Penghui,et al."Zika Virus Attenuation by Codon Pair Deoptimization Induces Sterilizing Immunity in Mouse Models".JOURNAL OF VIROLOGY 92.17(2018):16.