SaRNA (self-amplifying RNA) vaccines are created with the dual purpose of reducing the amount of genetic material inoculated with the vaccination and simultaneously generating large amounts of viral antigens to achieve a strong immune system response. The platform of these vaccines is based on the genome of a specific, suitably modified alphavirus: the Venezuelan equine encephalitis virus VEEV, consisting of a positive single-stranded RNA of about 11 Kbases. It is organized into two open reading frames (ORFs); the first encodes for 4 non-structural proteins that constitute an RNA-dependent RNA polymerase (replicase), the second encodes for the virus’ structural proteins, which make-up the capsid and envelope glycoproteins. Once assembled, the viral replicase is able to replicate the entire genome (called replicon, i.e. a sequence of genetic material able to replicate itself) in thousands of copies and the researchers thought to exploit this feature by modifying the genome of appropriate strains of VEEV preserving the non-structural replicase genes and by replacing the structural proteins genes with the sequence of a protein of a specific virus, called gene of interest (GOI), capable of behaving like an antigen and triggering a strong immune system response. The self-amplification of this structure within the host cell results in the synthesis of very large amounts of reference antigen, much higher than those synthesized by current mRNA vaccines, thus allowing the inoculation of smaller amounts of encapsulated genetic material carried in lipid nanoparticles (LNPs). In view of the current spread of SARS-CoV-2, the first saRNA vaccine produced and approved worldwide involved the insertion of the RNA sequence encoding for the spike protein as a GOI within the replicon. However, concerns have been raised in the international scientific world regarding the self-amplification mechanism of saRNA vaccines: the aim of this paper is to demonstrate that the self-replication mechanism of the saRNA vaccines is controlled and self-limiting.
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