Vaccine Booster's Secret Revealed

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http://sciencenow.sciencemag.org/cgi/content/full/2008/521/4Vaccine Booster's Secret RevealedBy EnserinkScienceNOW Daily News21 May 2008For decades, scientists have known that they can make vaccines much moreefficacious by adding aluminum compounds, but they never knew why. Now, astudy reveals how, on a molecular level, these helpers spur the productionof antibodies. The finding may help researchers develop better vaccines. Many vaccines contain adjuvants, nonspecific agents that help jolt theimmune system into action. "Alum," a term referring broadly to aluminumhydroxide and several aluminum salts, has this effect, as was accidentallydiscovered in the 1920s. It has been widely used in human vaccines since the1950s, and it's still the only adjuvant allowed in the United States. "Butwe didn't really have

a clue about how it worked," says immunologist HarmHogenEsch of Purdue University's School of Veterinary Medicine in WestLafayette, Indiana. The dominant theory held that alum particles bind theantigen--the vaccine's main ingredient--on their surfaces, presenting themmore slowly to the immune system and thus ensuring a more thorough response.But the situation is more complicated than that. Last year, HogenEsch's teamand a group led by Fabio Re at the University of Tennessee Health ScienceCenter in Memphis showed that in macrophages--white blood cells that gobbleup pathogens and cellular detritus--alum triggers the production ofinterleukin 1â and interleukin 18, two key signaling molecules, or cytokinesknown to stimulate the production of antibodies. Researchers knew that thisduo 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

wasinvolved. That race was won by a team led by Flavell of Yale University. Inthis week's issue of Nature, Flavell's group reports that aluminum adjuvantstrigger a NOD-like receptor called the Nalp3 inflammasome--an intracellularprotein structure that plays a key role in immune activation. When the groupinjected mice lacking Nalp3 with an alum-boosted vaccine, they producedalmost no antibodies; but a vaccine with another adjuvant called Freund'sresulted in the usual, vigorous immune response. Fe says he will publish thesame result in a paper accepted by the Journal of Immunology, which alsoshows that two other adjuvants--QuilA and chitosan--work in the same way. The Nalp3 inflammasome is known to be activated by compounds of microbialorigin and also by molecules that appear when cells die, such as uric acid.So researchers think that Nalp3 is like a "danger sensor," says Yaleimmunologist 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 specificadjuvants that are more effective or have fewer side effects, HogenEsch saysAlum, for instance, is known to kill muscle cells when injected intomuscles, as many vaccines are.------------------------------------

[Guest guest]

http://sciencenow.sciencemag.org/cgi/content/full/2008/521/4Vaccine Booster's Secret RevealedBy EnserinkScienceNOW Daily News21 May 2008For decades, scientists have known that they can make vaccines much moreefficacious by adding aluminum compounds, but they never knew why. Now, astudy reveals how, on a molecular level, these helpers spur the productionof antibodies. The finding may help researchers develop better vaccines. Many vaccines contain adjuvants, nonspecific agents that help jolt theimmune system into action. "Alum," a term referring broadly to aluminumhydroxide and several aluminum salts, has this effect, as was accidentallydiscovered in the 1920s. It has been widely used in human vaccines since the1950s, and it's still the only adjuvant allowed in the United States. "Butwe didn't really have

a clue about how it worked," says immunologist HarmHogenEsch of Purdue University's School of Veterinary Medicine in WestLafayette, Indiana. The dominant theory held that alum particles bind theantigen--the vaccine's main ingredient--on their surfaces, presenting themmore slowly to the immune system and thus ensuring a more thorough response.But the situation is more complicated than that. Last year, HogenEsch's teamand a group led by Fabio Re at the University of Tennessee Health ScienceCenter in Memphis showed that in macrophages--white blood cells that gobbleup pathogens and cellular detritus--alum triggers the production ofinterleukin 1â and interleukin 18, two key signaling molecules, or cytokinesknown to stimulate the production of antibodies. Researchers knew that thisduo 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

wasinvolved. That race was won by a team led by Flavell of Yale University. Inthis week's issue of Nature, Flavell's group reports that aluminum adjuvantstrigger a NOD-like receptor called the Nalp3 inflammasome--an intracellularprotein structure that plays a key role in immune activation. When the groupinjected mice lacking Nalp3 with an alum-boosted vaccine, they producedalmost no antibodies; but a vaccine with another adjuvant called Freund'sresulted in the usual, vigorous immune response. Fe says he will publish thesame result in a paper accepted by the Journal of Immunology, which alsoshows that two other adjuvants--QuilA and chitosan--work in the same way. The Nalp3 inflammasome is known to be activated by compounds of microbialorigin and also by molecules that appear when cells die, such as uric acid.So researchers think that Nalp3 is like a "danger sensor," says Yaleimmunologist 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 specificadjuvants that are more effective or have fewer side effects, HogenEsch saysAlum, for instance, is known to kill muscle cells when injected intomuscles, as many vaccines are.------------------------------------