Alum: an old dog with new tricks

Aluminum compounds (alum) are the most widely used adjuvants in veterinary and human vaccines. Alum was initially thought to be a simple depot for antigen retention; however, our understanding of the mechanism by which it works has progressed substantially in recent decades. Nonetheless, consensus regarding its roles in different aspects of immune regulation has not been reached, and it remains a long-standing research subject in the field of vaccinology. This review, in chronological order, discusses the various hypotheses proposed in mostly inadequate attempts to illuminate the mechanism by which alum works, from the depot theory to the involvement of the NLRP3 inflammasome and from cell death-associated danger factors to crystalline structure-mediated plasma membrane alteration. In addition, novel findings of unexpected beneficial effects of decreased HBV (Hepatitis B virus) viral load and HBeAg seroconversion in chronically infected patients, as well as significant tumor suppression in experimental mice following multiple alum-only injections are examined, revealing alum's potential clinical applications beyond its use as a simple tool in antigen preparation. With increasing threats of emerging microbes, originating from natural or man-made sources, that pose significant health concerns at the population scale, the potential use of alum as a ‘first-aid' vaccine is also discussed.