We developed innovative self-Amplifying mRNA (sa-mRNA) vaccine based on the derivative of S and Nsp3 proteins, which are considered crucial adhering to human host cells. We performed B-cell, Major histocompatibility complex (MHC) I, and II epitope which were merged with the KK and GPGPG linker. We also incorporated 5 cap sequence, Kozak sequence, replicase sequence, 3/5 UTR, and poly A tail within the vaccine structure. The vaccine structure was subsequently docked and run the molecular dynamic simulation with TLR7 molecules. As the results of immune response simulation, the immune response was accelerated drastically up to >10-fold for immunoglobulin, interferon-γ, interleukin-2, immunoglobulin M (IgM) + immunoglobulin G (IgG) isotype, IgM isotype, and IgG1 isotype in secondary and tertiary dose, whereas natural killer cells, macrophages, and dendritic cells showed relatively high concentrations after the first dose. As our finding, the IgM + IgG, IgG1 + IgG2, and IgM level (induced by sa-mRNA vaccine) ensued three times with two-fold increase in days 25, and 50, then decreased after days 70-150. However, 150-350 days demonstrated constantly in the range of 20,000-21,000. © 2024 Journal of Advanced Pharmaceutical Technology & Research.