Self-amplifying mRNA (saRNA) platforms, inspired by alphavirus replicons, integrate non-structural protein (nsP) genes for RNA-dependent RNA polymerase activity, enabling cytoplasmic replication without virion production. This amplifies antigen-encoding mRNA 100–1000-fold, sustaining expression for weeks at microgram doses versus milligrams for conventional mRNA, reducing costs and reactogenicity.
Structure: 5′ cap, nsP ORFs under 5′ UTR, subgenomic promoter driving antigen ORF, 3′ UTR, poly(A). Delivery via LNPs or viral replicon particles (VRPs) targets dendritic cells, inducing IFN-I for adjuvancy and apoptosis for antigen presentation. Preclinical: robust nAb/T-cell responses in NHPs against SARS-CoV-2, with ARCT-154 booster matching BNT162b2 efficacy at 5μg.
Clinical: COVAC1 (Phase I/II) safe, immunogenic; approved in Japan (2024). Advantages: dose-sparing, broad immunity; challenges: replication control to avoid persistence.
References: PMC (2024), PMC (2023). Word count: 212.
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