Towards an understanding of the adjuvant action of aluminium

Abstract

The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work.

Figure 1. Activation of the NLRP3 inflammasome by aluminium salts

(1) Aluminum salt cytotoxicity leads to release of DAMPs such as uric acid by the necrotic cell. At high concentrations, uric acid forms monosodium urate (MSU) crystals. (2a) MSU crystals are phagocytosed by resident cells. (2b) In addition or alternatively, aluminum adjuvants are directly phagocytosed by resident cells. (3) MSU or aluminium salts disrupt lysosomes, releasing cathepsin B. (4) Cathepsin B may directly or indirectly induce K+ efflux which (5) co-activates the NLRP3 inflammasome. (6) An unknown signal induces the production of pro-IL-1β, pro-IL-18 and pro-IL-33. (7) caspase-1, following activation by the NLRP3 inflammasome, cleaves pro-IL-1β, pro-IL-18 and pro-IL-33 to their active forms thereby promoting their secretion.

Box 2

The NALP3 inflammasome