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.
That race was won by a team led by Richard Flavell of Yale University. In this week's issue of Nature, Flavell's group reports that aluminum adjuvants trigger a NOD-like receptor called the Nalp3 inflammasome--an intracellular protein structure that plays a key role in immune activation. When the group injected mice lacking Nalp3 with an alum-boosted vaccine, they produced almost no antibodies; but a vaccine with another adjuvant called Freund's resulted in the usual, vigorous immune response. Re says he will publish the same result in a paper accepted by the Journal of Immunology, which also shows that two other adjuvants--QuilA and chitosan--work in the same way.
The Nalp3 inflammasome is known to be activated by compounds of microbial origin and also by molecules that appear when cells die, such as uric acid. So researchers think that Nalp3 is like a "danger sensor," says Yale immunologist Stephanie Eisenbarth, the first author on the Nature paper. Alum-containing vaccines may simply "hijack" that response.
Knowing how alum works its magic may help researchers design more specific adjuvants that are more effective or have fewer side effects, HogenEsch says. Alum, for instance, is known to kill muscle cells when injected into muscles, as many vaccines are.