In 1994, the concept of self-amplifying mRNA (saRNA) was first used with the application of Semliki Forest Virus (SFV). And other well-researched alphaviruses like Sindbis virus and Venezuelan equine encephalitis virus are also applied for saRNA production. saRNA, just like non-amplifying mRNA, comprises a 5’ cap, 5’-UTR, open reading frame (ORF) region, 3’-UTR, and 3’ poly(A) tail.
But for the reason that ssRNAs can self-replicate with the help of a replicase located downstream of the 5'-UTR, they differ significantly from non-amplifying mRNAs. There are four non-structural proteins (nsP1, nsP2, nsP3, and nsP4) secreted from alphaviruses. nsP1 has GTase and N7MTase activity, and nsP2 shows RTPase activity and caps the IVT mRNA to form Cap 0. As a protease and helicase, nsP2 also facilitate the processing of the entire nsP complex. nsP3 plays a role in inhibiting the antiviral response by interacting with several host cell proteins. The most conserved protein in alpha-viruses is nsP4, which provides RNA-dependent RNA polymerase (RdRp) function and increases the copy number of original ITV mRNA.
This viral protein is highly immunogenic, with a coding sequence of more than 7,000 base pairs, which limits the size of the antigen in such vaccines.
Application of saRNA
saRNA Vaccines Against Virus Pathogens
In September 2023, Arcturus Therapeutics and CSL announced that the EMA approves its Marketing Authorization Application (MAA) for ARCT-154 Vaccine, a self- amplifying mRNA (sa-mRNA) vaccine for the prevention of COVID-19. Arcturus and CSL expect an approval decision by the European Commission in 2024. Japan's MHLW approved ARCT-154 in Dec 2023.
The ARCT-154 vaccine is based on Venezuelan equine encephalitis virus (VEEV) and consists of a replicon in which the structural proteins of VEEV are replaced by the core proteins of SARS-CoV-2. Compared to first-generation mRNA vaccine booster, ARCT-154 shows non-inferiority to original strain and superior immunogenicity to omicron BA.4/5 variant.
Several other saRNA-based vaccines are in clinical or preclinical trials. These vaccines target pathogens, including SARS-CoV-2, influenza virus, rabies virus, Zika virus, Ebola virus, VEEV, HIV-1, and certain microbes causing bacterial infections or parasitic infestations, as well as cancer.
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