RNA replicons are derived from either positive- or negative-strand RNA viruses, from which at least one gene encoding an essential structural protein has been deleted. RNA replicons can be regarded as disabled viruses unable to produce infectious progeny. Despite such gene deletions, the viral RNA is replicated and transcribed by the viral RNA polymerase. Any genetic information encoded by the replicon will be amplified many times, resulting in high levels of antigen expression. This property distinguishes RNA replicons from plasmid DNA-based vaccines, which rely on the initial levels of genetic information successfully delivered to the nucleus. The latter together with the characteristics of DNA replication can prove to be a major hurdle for advancing DNA vaccines. Vaccines based on DNA plasmids often contain regulatory sequences and antibiotic resistance genes. The potential integration of such sequences into the host genome by non-homologous recombination may represent an unknown risk. In contrast, replication/transcription of replicon RNA is strictly confined to the cytosol, and does not require any cDNA intermediates, nor is any recombination with or integration into the chromosomal DNA of the host required. Taken together, several safety issues are associated with DNA vaccines, which do not arise with the much more biosafe RNA-based vaccines. Due to autonomous RNA replication, RNA replicons are able to drive high level, cytosolic expression of recombinant antigens stimulating both the humoral and the cellular branch of the immune system. This review provides an update on the available literature covering influenza virus vaccines based on RNA replicons. The pros and cons of this vaccine strategies are discussed.
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