Abstract: First-generation COVID-19 vaccines exhibited significant limitations in countering continuous pathogen evolution and intercepting viral transmission. To develop pan-coronavirus vaccines with cross-variant protective efficacy, this review provided a systematic discussion of research and development strategies, ranging from antigen design to delivery system optimization. The analysis focused on antigen engineering based on S2 subunit conformational remodeling and multi-epitope recombination, while exploring the mechanisms of immune response modulation via multivalent display on protein nanoparticles, viain situexpression using mRNA platforms, and via efficient transduction with viral vectors. Regarding localized respiratory defense, the review elaborated on mucosal immunity strategies to overcome mucosal tolerance and induce secretory IgA and tissue-resident memory cells, further emphasizing the necessity of establishing standardized clinical evaluation systems such as the identification of correlates of protection. In conclusion, integrating structural immunology, advanced delivery platforms, and regulatory science to construct a proactive pan-coronavirus vaccine framework is the pivotal direction for addressing future threats from novel variants and cross-species transmission.

Key words: pan-coronavirus vaccines, antigen engineering, delivery systems, mucosal immunity, correlates of protection