Adjuvants, the Elephant in the Room for RNA Vaccines

Adjuvants are crucial components of vaccines. Nevertheless, they are frequently considered as mere “excipients”, and their mode of action is often poorly understood. Although the attractiveness of mRNA as an immunogen has been recognized already more than thirty years ago, it wasn’t until the current COVID-19 crisis that its full potential was shown. From a fringe approach, it has now become a leading technology in vaccine development which will no doubt result in a tremendous boost in both prophylactic and therapeutic vaccination settings. The issue of finding the right adjuvant is especially relevant for mRNA-based vaccines, as mRNA itself is a strong activator of innate immune responses which represents a double-edged sword. Moreover, given the high sensitivity of RNA to ambient RNases, and to improve delivery efficiency, in recent years, a lot of effort has been invested in developing ways to package the mRNA in so-called nanoparticle formulations. Currently approved mRNA-based vaccines are all formulated in lipid nanoparticles, but many other approaches are being explored, each of which will result in a different type of immune stimulation. In this chapter, we want to provide an overview of the potential adjuvant effect of different types of nanoparticles and implications for vaccine development.