Rise of the RNA machines - self-amplification in mRNA vaccine design

mRNA vaccines have won the race for early COVID-19 vaccine approval, yet im-provements are necessary to retain this leading role in combating infectious dis-eases. A next generation of self-amplifying mRNAs, also known as replicons, form an ideal vaccine platform. Replicons induce potent humoral and cellular re-sponses with few adverse effects upon a minimal, single-dose immunization. De-livery of replicons is achieved with virus-like replicon particles (VRPs), or in nonviral vehicles such as liposomes or lipid nanoparticles. Here, we discuss in-novative advances, including multivalent, mucosal, and therapeutic replicon vaccines, and highlight novelties in replicon design. As soon as essential safety evaluations have been resolved, this promising vaccine concept can transform into a widely applied clinical platform technology taking center stage in pan-demic preparedness.