COVID-19 mRNA vaccines: a prospective outlook from technological innovation to clinical practice

The COVID-19 pandemic established mRNA vaccines as a clinically validated platform for rapid vaccine development and deployment. This review summarizes recent progress in COVID-19 mRNA vaccine technology, clinical performance, immunological mechanisms, and translational applications. First-generation nucleoside-modified mRNA vaccines formulated in lipid nanoparticles demonstrated strong protection against symptomatic disease and, more durably, against severe outcomes, while variant-driven immune escape, waning protection against infection, limited mucosal immunity, and heterogeneous responses in special populations revealed important constraints. The review compares mRNA vaccines with other COVID-19 vaccine platforms and clarifies endpoint-specific correlates of protection, emphasizing the distinct roles of neutralizing antibodies, memory B cells, T-cell responses, and non-neutralizing antibody functions. It further examines unresolved issues associated with repeated vaccination, including immune imprinting and IgG4 class switching, and evaluates technological strategies designed to improve durability, breadth, delivery, and immune programming. Key innovations include optimized RNA chemistry, structure-guided antigen design, advanced lipid nanoparticle formulations, alternative delivery systems, immune-shaping adjuvant approaches, and next-generation RNA formats such as self-amplifying RNA and circular RNA. Finally, the review discusses vaccination strategies for immunocompromised individuals, pregnant and lactating women, older adults, and children, as well as the expansion of mRNA technology into respiratory virus vaccines, cancer immunotherapy, and therapeutic protein expression. These developments define mRNA technology as a modular platform whose clinical impact depends on aligning RNA architecture, delivery system, antigen design, and target population.