alum: Vaccine Booster's Secrets Revealed - bonus: alum kills muscle cells

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Vaccine Booster's Secret Revealed

By Enserink

/Science/NOW Daily News

21 May 2008

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

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 1? 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. 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 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.

More about vaccine adjuvants, including alum

<http://www.immunizationinfo.org/vaccine_components_detail.cfv?id=61>

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