Immunology of RNA-based vaccines: The critical interplay between inflammation and expression

Since its use during the COVID-19 pandemic, mRNA has emerged as a leading candidate vaccine platform for pandemic infections. A critical difference between RNA-encoded antigen and protein vaccines is that RNA-based vaccines require the antigen to be translated in the body, adding an important variable. Much of the research focus in the field has been on ways to increase expression, but inflammation plays a critical role. The vaccine delivered is a combination of the RNA and the formulation, so both elements need to be considered. Formulated RNA can act as a form of adjuvant but can also activate cellular pathways that inhibit expression. Expression and inflammation are interlinked, but independent-a deeper understanding of the quality and quantity of immune induction will help to develop more efficient RNA vaccines. Here, we discuss factors that shape responses to RNA-based vaccines. These include the composition of the vaccine (the use of modified RNA bases, whether self-replicating or traditional mRNA and, critically, the formulation) and the type of cells that take up and translate the RNA. We then consider challenges presented by current generation RNA vaccines including clinical impact and how improved immunological understanding can inform the development of improved RNA vaccine platforms.