Synthetic rational design of live-attenuated Zika viruses based on a computational model

Abstract

Many viruses of the Flaviviridae family, including the Zika virus (ZIKV), are human pathogens of significant public health concerns. Despite extensive research, there are currently no approved vaccines available for ZIKV and specifically no live-attenuated Zika vaccine. In this current study, we suggest a novel computational algorithm for generating live-attenuated vaccines via the introduction of silent mutation into regions that undergo selection for strong or weak local RNA folding or into regions that exhibit medium levels of sequence conservation. By implementing our approach to the ZIKV genome, we demonstrated strong correlation between the degree of conserved RNA local energy disruption and replicative ability of the viruses in Vero cells. In vivo analysis in the AG129 mouse model demonstrated the ability of the attenuated ZIKV strains to stimulate protective immune response against the wild-type virus. In some cases, up to 80% of the AG129 mice survived both the vaccination and the challenge with the wild-type strains, while 0% of the nonvaccinated mice survived the challenge. Our study provides a blueprint for a computational design of live-attenuated vaccine strains that still preserve immunogenic epitopes of the original RNA viruses. We believe that the approach is generic and can be used successfully for additional viruses.