Improving the safety of live attenuated viral vaccines by exploiting RNA silencing pathways

Live-attenuated viral vaccines are among the most successful vaccine approaches and have been used for decades. However, live-attenuated vaccines come with a risk of reversion or recombination of the vaccine to a virulent form. An important consideration for live-attenuated vaccines for arthropod-borne (arbo-) viruses is that they should not replicate in their mosquito vectors to prevent unwanted spread of the vaccine and vaccine-derived virulent strains. In this ERC Proof-of-Concept project (VIVARNAsilencing2), we will develop an innovative approach to enhance the safety of live-attenuated vaccines for mosquito-transmitted viruses, by preventing their replication in mosquitoes. To this end, we will exploit a small RNA-based gene regulatory network of the mosquito vector to target viral RNA for degradation in the mosquito. The mechanism and natural function of this gene regulatory network had been characterized in an ERC Consolidator Grant, which we will now develop into a commercial and societal valuable product. We will focus on important epidemic human arboviruses with a large disease burden such as dengue virus, Zika virus, and chikungunya virus, but the approach is readily applicable for all arboviruses that are transmitted by mosquitoes of the Culex and Aedes genera, including pathogens of livestock. VIVARNAsilencing2 meets an urgent need in the face of the enormous disease burden and strong global push to develop vaccines for the important class of mosquito-transmitted pathogens.