Emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants have raised concerns about the efficacy of vaccines. The present study aimed to compare the potential of Delta and Omicron variant-specific mRNA vaccines in inducing immune responses. B cell and T cell epitopes and population coverage of spike (S) glycoprotein of the variants were predicted using the Immune Epitope Database. The molecular docking was carried out between the protein and different toll-like receptors, as well as the receptor-binding domain (RBD) protein and angiotensin-converting-enzyme 2 (ACE2) cellular receptor using ClusPro. The molecular simulation was done for each docked RBD-ACE2 using YASARA. The mRNA secondary structure was predicted through the RNAfold. The simulation of immune responses to the mRNA vaccine construct was performed using C-ImmSim. Apart from a few positions, no significant difference was observed in the prediction of S protein B cell and T cell epitopes of these two variants. The lower amounts of Median consensus percentile in the Delta variant in similar positions signify its stronger affinity to major histocompatibility complex (MHC) II binding alleles. Docking of Delta S protein with TLR3, TLR4, and TLR7 and also its RBD with ACE2 showed striking interactions with the lower binding energy than Omicron. In the immune simulation, elevated levels of cytotoxic T lymphocytes, helper T lymphocytes, and memory cells in both the active and resting states and the main regulators of the immune system suggested the capacity of mRNA constructs to elicit robust immune responses against SARS-CoV-2 variants. Considering slight differences in the binding affinity to MHC II binding alleles, activation of TLRs, mRNA secondary structure stability, and concentration of immunoglobulins and cytokines, the Delta variant is suggested for the mRNA vaccine construction. Further studies are being done to prove the efficiency of the design construct.