OZR Back-up mandate: Nanoparticle-encapsulated self-replicating mRNA-based vaccination as a novel therapeutic approach against HIV

Despite the fact that therapeutic vaccines against HIV based on ex vivo modified dendritic cells have shown to be very promising, several disadvantages are associated with this approach. First, the development of a patient specific cellular vaccine requires significant expertise and specialized infrastructure. Furthermore, a significant financial cost is associated with this approach. Therefore, we and others looked into the possibility to develop mRNA-based vaccines
for application in vivo. We found that this approach is feasible and leads to antigen-specific immune responses. However, appropriate formulation of the mRNA is of the utmost importance for efficient delivery. Another disadvantage of mRNA is that the efficiency is very much dependent on the amount that is eventually delivered to the cell of interest. In order to address this issue, so-called selfreplicating mRNA has been developed by modifying the genome of single
stranded RNA viruses such as alphaviruses by replacing the structural genes by a transgene of choice. So far, this approach has not been extensively tested, and within the context of HIV only a handful of publications are available. Furthermore, similar issues as for mRNA apply to srRNA and therefore it is crucially important to develop appropriate formulations for efficient delivery of srRNA via the appropriate route. In this project we wish to evaluate several
candidate nanoparticles for formulation of srRNA expressing HIVantigens.