Like non-amplifiable mRNAs, sa-RNA consists of a 5' cap, a 5' UTR, an ORF (open reading frame) region, a 3' UTR, and a 3' poly(A) tail. While saRNA is very different from non- amplifying mRNA in that it contains the replicase coding sequence of downstream of the 5'UTR. With encoding sequences exceeding 7000 nucleotides, viral proteins are highly immunogenic, thus limiting the size of the antigen in such vaccines.
TaRNA is a type of saRNA in which the viral sequence, nsPs, and the gene of interest (GOI) are involved in different mRNAs but are functioned together. Pirjo Spuul et al. introduced the concept of a trans-replication system for the first time in 2011.
Viral replicase can be nrRNA or saRNA, and mRNAs encoding GOIs are named trans-replicons (TR-RNAs). To make TR-RNA amplification, conserved sequence elements (5’CSE and 3’CSE) come from the alphavirus flank the GOI, with SGP of the alphavirus upstream of the GOI. The design of taRNA takes into account the advantages of saRNAs and alleviates some of their disadvantages. In particular, stand-alone replicases encoding in an RNA platform avoid the limitations of GOIs length and do not restrict the use of modified nucleotides.
Further advances in taRNA technology have resulted in the development of an improved taRNA with an adenine-rich region in the 5' UTR. This revised taRNA’s lacking the subgenomic promoter of alphaviruses results in a shorter RNA and a 10-fold decrease in vaccine dose, without affecting in vitro expression levels.
Overall, taRNA technology is still in its infancy, but its practical applications are promising. Preclinical studies of taRNA vaccines against influenza viruses are currently underway. Bivalent vaccines against chikungunya and Ross River viruses are also under development in this way.
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