Immunogenicity and protection efficacy of self-amplifying and circular mRNA vaccines for SARS-CoV-2

Abstract Recent studies have demonstrated safety and reliability of messenger RNA (mRNA) vaccines for human use. Conventionally, mRNA vaccines use linear or self-amplifying mRNA (SAM), the latter considered to be superior. However, COVID-19 SAM vaccines showed limited success. Further, Circular mRNA (Circ-RNA) vaccines against the SARS-CoV-2, Ebola and monkey pox proved its efficacy. Circ-RNAs are highly stable, do not induce innate immune pathway RNA sensors nor require any extracellular protein for their function. Here, we compared the efficacy of SAM- and Circ-RNA vaccines using the SARS-CoV-2-RBD (receptor binding domain) antigen. Both SAM-RBD and Circ-RBD induced a comparable anti-RBD IgG titer and virus-neutralization titer. However, the latter induced a significantly higher memory T-cell response. Circ-RBD formulation was stable in refrigerator, induced a durable neutralizing antibody response, protected mice from COVID-19-like pathology and a bivalent vaccine containing the Circ-RNA-RBD of SARS-CoV-2-Delta and Omicron variants potently neutralized both viruses. These finding demonstrate the overall superiority of the Circ-RNA over the SAM vaccine technology and provides the proof of concept for developing bivalent Circ-RNA vaccines against emerging variants of SARS-CoV-2.