Combination adjuvants: clinical value and mechanisms of action.

Combination adjuvants enhance vaccine immunogenicity by integrating multiple immunostimulatory signals that shape both innate and adaptive immune responses. In this review, we summarize the clinical evidence supporting the added value of combination adjuvants, including aluminum-Toll-like receptor ligand formulations, oil-in-water emulsions containing immunostimulatory molecules, and saponin-based systems. We further discuss how the most recent mechanistic studies have shown that combination adjuvants act through additive or synergistic effects, engaging distinct molecular and cellular pathways to shape innate immune activation. Moreover, we propose that mRNA vaccines represent a new class of functional combination adjuvants, integrating both mRNA sensing and lipid nanoparticle-driven inflammation. Together, the current evidence supports the value of combination adjuvants in optimizing vaccine responses and underscores the need to continuously understand their mode of action to enable rational adjuvant design.