Modified mRNA Vaccines Protect against Zika Virus Infection.
Modified mRNA Vaccines Protect against Zika Virus Infection.
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DOI：
10.1016/j.cell.2017.02.017
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发表时间：
2017-03-09
期刊：
影响因子：
64.5
通讯作者：
Diamond MS
中科院分区：
文献类型：
--
作者：
Richner JM;Himansu S;Dowd KA;Butler SL;Salazar V;Fox JM;Julander JG;Tang WW;Shresta S;Pierson TC;Ciaramella G;Diamond MS
ZIKV感染的出现促使全球努力开发安全有效的疫苗。我们设计了一种脂纳米颗粒(LNP)包裹的编码野生型或变异型ZIKV结构基因的修饰的mRNA疫苗，并在小鼠身上测试了免疫原性和保护性。两个剂量的编码PrM-E基因的修饰mRNA LNPs可产生高中和抗体效价(~1/100,000)，可保护ZIKV感染并产生灭菌免疫。为了消除ZIKV疫苗诱导抗体与相关登革病毒(DENV)发生交叉反应的理论担忧，我们设计了编码突变的PRM-E RNA，以破坏E蛋白中保守的融合环表位。这种变异体可以抵抗ZIKV，并减少细胞或小鼠体内增强DENV感染的抗体的产生。改良的信使核糖核酸疫苗可以预防ZIKV疾病，如果这成为临床相关的问题，可以调整以降低个体对随后暴露于DENV的敏感风险。一种经过修改的mRNA疫苗可以诱导对寨卡病毒的灭菌免疫，同时避免产生可能会加剧登革热感染的交叉反应抗体。
The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (~ 1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related Dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically-relevant concern. A modified mRNA vaccine induces sterilizing immunity against Zika virus while avoiding the generation of cross-reactive antibodies that may enhance dengue infection.