Study Injects New Interest In How Vaccines Work

July 03, 1997

WEST LAFAYETTE, Ind. -- A popular theory about how a major component of vaccines works within the body has been shot down by a Purdue University study.

Purdue researcher Stanley Hem has found that aluminum hydroxide, a small particle used to carry antigens into the body to boost an immune response, begins to dissolve in the muscle immediately after an injection and is eliminated from the body hundreds of times faster than presumed.

"Aluminum hydroxide is used in vaccines to increase the body's production of antibodies, though no one knows how it works," says Hem, professor of industrial and physical pharmacy. "The most popular theory was that it remained in the muscle for months while the body produced antibodies in response to the antigens carried on its surface."

The study raises new questions about the mechanism by which aluminum hydroxide works, Hem says. The findings will appear in the September issue of the British scientific journal Vaccine.

During the 1930s, researchers discovered that using aluminum hydroxide to carry antigens into the body resulted in a greater production of antibodies than could be produced by the antigen alone. Antibodies are proteins made by the immune system to fight off foreign substances. Antigens -- the proteins or molecules that stimulate the immune system to create antibodies -- are condensed and collected on the surface of aluminum hydroxide particles.

Since 1934, aluminum hydroxide has been used as an adjuvant to boost the immune response from vaccines. Currently, it is the only adjuvant approved by the Food and Drug Administration for use in human vaccines. The FDA limits the dosage to 0.85 milligrams per vaccine to minimize exposure to aluminum.

"There's been some interest in other materials, but no one has proven them safe enough," Hem says.

Though scientists have puzzled over the mechanism by which aluminum hydroxide increases the production of antibodies, the tiny amounts of the substance used in vaccines made it impossible to track or analyze it once it was injected into the body, Hem says.

"The most popular theory was that it created a 'depot effect,' where the aluminum hydroxide particles served as a storehouse for the antigen and stayed in the muscle for many months while the body continually produced antibodies," Hem says.

Though this explanation was generally accepted, Hem says he questioned how aluminum particles could stay in the muscle for great lengths of time. "The fluid in our muscles, called interstitial fluid, contains citrate, and citrate can dissolve aluminum," he says, "This made me suspect that these aluminum particles didn't stay in muscle for months, because they are continually washed with interstitial fluid."

Hem also questioned why the body did not create a wall around the particles, as would be expected when a particle remained in the muscle for a long period of time.

"Generally, if you have particles in your muscles for a long time, the body will wall them off and make a nodule or lump," Hem says. "You would expect to see a lot of lumps and nodules in the spot where people get vaccinated, but there are very few reports of such nodules at the site of vaccination."

Though these questions nagged him for years, Hem said he didn't have a way of testing the theory until a few years ago, when Purdue established a laboratory for accelerator mass spectrometry. AMS, a technique that uses an atomic accelerator and a mass spectrometer to separate and measure the various components in a sample, is capable of obtaining accurate measurements of molecules that are present in minuscule proportions.

"The technique is so sensitive, it can detect the equivalent of a single grain of sand in a football stadium filled with sand," Hem says.

Hem and Purdue physicist David Elmore assembled an interdisciplinary team and designed an experiment to see how quickly aluminum hydroxide was eliminated from the body and to track the amounts of the substance that remained in vaccinated tissue over a period of time.

They developed a series of rabbit vaccines containing a small amount of aluminum-26, a form of aluminum that is not found in nature. By incorporating aluminum-26 along with aluminum-27 -- the naturally occurring form of aluminum found in small amounts in human and animal tissue -- Hem was able to extrapolate how much of the aluminum in the vaccine the rabbit was eliminating.

His study found that aluminum-26 was present in blood samples one hour after the vaccine was injected into the rabbits' muscles, and appeared in urine samples after just four hours.

"This means that the particles are dissolving almost immediately because of the citrate in the interstitial fluid," Hem says, "and indicates that the aluminum is not going to stay in muscle for a long period of time.

"If the aluminum adjuvant in the body is starting to dissolve within an hour, it's likely that whatever was collected on the surface is being released within a fairly short time."

Though he does not have an alternative theory to explain how aluminum hydroxide works to boost antibody production, Hem says that his study may spur new interest into the mechanism behind this reaction.

"The study also explains why aluminum hydroxide adjuvants have such a good safety record," Hem says. "The aluminum hydroxide dissolves in the interstitial fluid and is excreted from the body by the kidney."

In addition to Hem and Elmore, the interdisciplinary team at Purdue included Richard Flack, graduate student in physics, Joe White, professor emeritus who specializes in mineralogy, Mark Suckow, lab animal veterinarian, Anita Rudy, pharmacokineticist from Indiana University Medical School, and Euphemie Dandashli, a Purdue chemist who worked with Hem to develop the adjuvants.

The study was funded by the Purdue University Research Foundation.
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Purdue University

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