Engineered alphavirus replicon vaccines based on known attenuated viral mutants show limited effects on immunogenicity

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• 作者：Giulietta Maruggi ; Christine A. Shaw ; Gillis R. Otten ; Peter W. Mason ; Clayton W. Beard
• 关键词：Alphavirus replicon vaccine ; 5&prime ; UTR ; Secondary structure ; Attenuating mutation ; Antigen expression ; Interferon induction
• 刊名：Virology
• 出版年：December, 2013
• 年：2013
• 卷：447
• 期：1-2
• 页码：254-264
• 全文大小：1114 K

文摘

The immunogenicity of alphavirus replicon vaccines is determined by many factors including the level of antigen expression and induction of innate immune responses. Characterized attenuated alphavirus mutants contain changes to the genomic 5鈥?UTR and mutations that result in altered non-structural protein cleavage timing leading to altered levels of antigen expression and interferon (IFN) induction. In an attempt to create more potent replicon vaccines, we engineered a panel of Venezuelan equine encephalitis-Sindbis virus chimeric replicons that contained these attenuating mutations. Modified replicons were ranked for antigen expression and IFN induction levels in cell culture and then evaluated in mice. The results of these studies showed that differences in antigen production and IFN induction in vitro did not correlate with large changes in immunogenicity in vivo. These findings indicate that the complex interactions between innate immune response and the replicon鈥瞫 ability to express antigen complicate rational design of more potent alphavirus replicons.