Madelon, N., Didierlaurent, A.M. Combination adjuvants: clinical value and mechanisms of action. Curr Opin Virol, 2026 Jun 19, 76:101564. PMID: 42320106

This review article highlights the mechanistic insights and clinical evidence supporting their use within combination formulations, such as AS01, which contains QS-21 saponins. It emphasizes how saponins synergize with other immunostimulants like MPL to induce early interferon responses, promote dendritic cell activation, and generate robust T-cell immunity, including polyfunctional CD4+ T cells and NK cell responses. The paper is unique in synthesizing recent advances in understanding how diverse combination adjuvants act through additive or synergistic pathways to modulate innate and adaptive immunity, providing a foundation for rational vaccine design. 

The authors conclude that combination adjuvants, notably those incorporating saponins such as QS-21 within AS01, demonstrate significant clinical value by inducing robust and diverse immune responses through additive and synergistic mechanisms that engage distinct molecular pathways. They emphasize the importance of understanding these mechanisms to optimize vaccine efficacy and safety. However, limitations include the current paucity of detailed human studies that definitively dissect the contribution of individual components within complex adjuvants and the variability in responses depending on the antigen, adjuvant formulation, and population. The authors advocate for further mechanistic studies, especially in humans, to confirm these pathways and to refine adjuvant design. Projected next steps involve rational development of adjuvants based on mechanistic insights, ongoing clinical trials to validate efficacy and safety, and exploration of combination adjuvants with novel components to address unmet vaccine needs.

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