The major histocompatibility complex class I (MHCI) trafficking signal (MITD)plays a pivotal role in enhancing the efficacy of mRNA vaccines. However, therewas a lack of research investigating its efficacy in enhancing immune responses toRNA virus infections. Here, we have developed an innovative strategy for the for-mulation of mRNA vaccines. This approach involved the integration of MITD intothe mRNA sequence encoding the virus antigen. Mechanistically, MITD-basedmRNA vaccines can strengthen immune protection by mimicking the dynamictrafficking properties of MHCI molecule and thus expand the memory specific Band T cells. The model MITD-based mRNA vaccines encoding binding receptor-binding domain (RBD) of SARS-CoV-2 were indeed found to achieve protectiveduration, optimal storage stability, broad efficacy, and high safety.