Vaccine Booster's Secret Revealed

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http://sciencenow.sciencemag.org/cgi/content/full/2008/521/4

Vaccine Booster's Secret Revealed

By Enserink

ScienceNOW Daily News

21 May 2008

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 1â 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 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. Fe 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 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.