Programming systemic and mucosal immunity through co-adjuvant-based prime-boost vaccination

The development of effective mucosal vaccines has been limited by the limited availability of mucosal adjuvant approaches with established clinical track records and an incomplete understanding of how systemic and mucosal immunity are coordinated. Recent studies indicate that the priming phase of vaccination plays a decisive role in programming the quality, durability, and anatomical distribution of subsequent immune responses. This review discusses emerging evidence that co-adjuvant-based priming strategies can establish long-lasting immune programs that enable adjuvant-free mucosal boosting. Focusing on the combination of CpG DNA and curdlan as a prototypical example, this review highlights how coordinated activation of innate immune receptors during priming imprints dendritic cells, B cells, and T cells to support robust mucosal IgA and tissue-resident immunity. This review further discusses translational advances demonstrating that this immune programming paradigm can be maintained using translationally oriented formulations designed with clinical development in mind and validated in non-human primates. Independent studies using mRNA and protein-based vaccines support the general principle that the quality of priming, rather than the boosting modality, determines successful mucosal immunity. Together, these findings redefine vaccine adjuvants as tools for immune programming and provide a conceptual framework for next-generation vaccine design.