Trans-Amplifying RNA Vaccines Against Infectious Diseases: A Comparison with Non-Replicating and Self-Amplifying RNA

The recent COVID-19 pandemic as well as other past and recent outbreaks of newly or re-emerging viruses show the urgent need to develop potent new vaccine approaches, that enable a quick response to prevent global spread of infectious diseases. The breakthrough of first messenger RNA (mRNA)-based vaccines 2019 approved only months after identification of the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), opens a big new field for vaccine engineering. Currently, two major types of mRNA are being pursued as vaccines for the prevention of infectious diseases. One is non-replicating mRNA, including nucleoside-modified mRNA, used in the current COVID-19 vaccines of Moderna and BioNTech (Sahin et al., Nat Rev Drug Discov 13(10):759-780, 2014; Baden et al., N Engl J Med 384(5):403-416, 2021; Polack et al., N Engl J Med 383(27):2603-2615, 2020), the other is self-amplifying RNA (saRNA) derived from RNA viruses. Recently, trans-amplifying RNA, a split vector system, has been described as a third class of mRNA (Spuul et al., J Virol 85(10):4739-4751, 2011; Blakney et al., Front Mol Biosci 5:71, 2018; Beissert et al., Mol Ther 28(1):119-128, 2020). In this chapter we review the different types of mRNA currently used for vaccine development with focus on trans-amplifying RNA.