Adjuvants are vaccine additives that stimulate the immune system without having any specific antigenic effect of itself. In this study we show that alum adjuvant induces the release of IL-1beta from macrophages and dendritic cells and that this is abrogated in cells lacking various NALP3 inflammasome components. The NALP3 inflammasome is also required in vivo for the innate immune response to OVA in alum. The early production of IL-1beta and the influx of inflammatory cells into the peritoneal cavity is strongly reduced in NALP3-deficient mice. The activation of adaptive cellular immunity to OVA-alum is initiated by monocytic dendritic cell precursors that induce the expansion of Ag-specific T cells in a NALP3-dependent way. We propose that, in addition to TLR stimulators, agonists of the NALP3 inflammasome should also be considered as vaccine adjuvants.

Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system1, 2. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.

Some vaccines and other medicines contain chemicals called adjuvants to help stimulate the production of immunity against the vaccine ingredients, making the vaccine more effective. The word ‘adjuvant’ is derived from the Latin word ‘adjuvare’ which means ‘to help’. Aluminum salts have frequently been incorporated as adjuvants in vaccines licensed for use in the United States and elsewhere. There are other adjuvants incorporated in vaccines licensed in other countries and there are other adjuvants used in other medications (which are not vaccines) that have been licensed in the United States. It is likely that other adjuvants will be incorporated in a number of new vaccines currently being tested for use in the United States.

For decades, scientists have known that they can make vaccines much more efficacious by adding aluminum compounds, but they never knew why. Now, a study reveals how, on a molecular level, these helpers spur the production of antibodies. The finding may help researchers develop better vaccines. Many vaccines contain adjuvants, nonspecific agents that help jolt the immune system into action. "Alum," a term referring broadly to aluminum hydroxide and several aluminum salts, has this effect, as was accidentally discovered in the 1920s. It has been widely used in human vaccines since the 1950s, and it's still the only adjuvant allowed in the United States. "But we didn't really have a clue about how it worked," says immunologist Harm HogenEsch of Purdue University's School of Veterinary Medicine in West Lafayette, Indiana. The dominant theory held that alum particles bind the antigen--the vaccine's main ingredient--on their surfaces, presenting them more slowly to the immune system and thus ensuring a more thorough response. But the situation is more complicated than that. Last year, HogenEsch's team and a group led by Fabio Re at the University of Tennessee Health Science Center in Memphis showed that in macrophages--white blood cells that gobble up pathogens and cellular detritus--alum triggers the production of interleukin 1β and interleukin 18, two key signaling molecules, or cytokines, known to stimulate the production of antibodies. Researchers knew that this duo is often released after the activation of so-called NOD-like receptors. "So then the race was on," says Re, to pinpoint which NOD-like receptor was involved.

Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines, but the mechanism of its adjuvanticity remains unknown. In vitro studies showed no stimulatory effects on dendritic cells (DCs). In the absence of adjuvant, Ag was taken up by lymph node (LN)–resident DCs that acquired soluble Ag via afferent lymphatics, whereas after injection of alum, Ag was taken up, processed, and presented by inflammatory monocytes that migrated from the peritoneum, thus becoming inflammatory DCs that induced a persistent Th2 response. The enhancing effects of alum on both cellular and humoral immunity were completely abolished when CD11c+ monocytes and DCs were conditionally depleted during immunization. Mechanistically, DC-driven responses were abolished in MyD88-deficient mice and after uricase treatment, implying the induction of uric acid. These findings suggest that alum adjuvant is immunogenic by exploiting "nature's adjuvant," the inflammatory DC through induction of the endogenous danger signal uric acid.

For more than 70 years, alum has been used as a trusty aide to improve antibody responses to vaccines. But how this aluminum-containing compound boosts the response to vaccines has been a mystery. Kool et al. expose its mysterious mechanism; they find that alum causes cells to produce a stimulator of dendritic cells (DCs). DCs were once the favored hypothetical link between alum and B cells, as they activate CD4+ T cells, which can then enhance B cell activation and antibody production. But DCs were later dismissed when it was found that they were not stimulated by alum in vitro. These in vitro results are now shown to be a red herring by Kool et al., who find that alum activates DCs in vivo by provoking the secretion of uric acid—a molecule that is triggered by tissue and cell trauma. The injection of alum, the group found, induced an influx of neutrophils and inflammatory cytokines and chemokines—a combination that was previously seen in response to the injection of uric acid into mice.