Aluminum-containing adjuvants: a problem?

January 2001

One of the more entertaining (scientifically entertaining) experiences I had in the year past was attendance at a workshop on aluminum-containing adjuvants in vaccines. The workshop was held in the felicitous environment of San Juan, Puerto Rico, last May, and was sponsored by the National Vaccine Program Office, a Health and Human Services-based office charged with coordination of the major federal players in the vaccine arena, namely, the National Institutes of Health, the Food and Drug Administration and the Centers for Disease Control and Prevention (CDC).

It was the second in a series of workshops that examined additives to vaccines. The first workshop, held the previous year, dealt with thimerosal, and exposed a great deal of scientific uncertainty extending in some areas to ignorance about the distribution and the behavior of the active compound, ethyl mercury.

The same pervasive uncertainty, bordering in some instances on ignorance, characterized the aluminum-containing adjuvants workshop.

Mechanism of action uncertain

There are three basic aluminum salts used as vaccine adjuvants: aluminum hydroxide, aluminum phosphate and potassium-aluminum sulfate, or alum. Each has different chemical properties and isoelectric points, and they are not simply interchangeable when used in vaccine formulations. The mechanism of action of these adjuvants represents an area of scientific uncertainty, but they are believed to form a repository of antigen in tissue, to facilitate presentation of particulate antigen to immune cells, and perhaps, to activate complement and other immune enhancers.

The goal of adjuvant use in vaccines is to enhance immune contact, to increase the height of the antibody response, and to prolong the immune response - all this, of course, with total safety and freedom from adverse effects. The aluminum-containing adjuvants have certainly succeeded as immune enhancers, and this is amply documented in the literature of the 1930s-1960s. The enhancement effect is most marked during the primary immunization series; there is little incremental benefit of aluminum adjuvants in booster doses. The adjuvants appear to facilitate a type 2 immunologic response and do not induce cytotoxic T cells and cell-mediated immune mechanisms. These adjuvants are, however, not totally free of adverse effects; sterile abscesses, erythema, swelling, subcutaneous nodules, granulomatous inflammation and contact hypersensitivity have been reported with variable frequency and severity.

U.S. licensed vaccines that contain aluminum salts include DTP, DTaP, some but not all Hib vaccines, and HepA and HepB, Lyme disease, anthrax and rabies vaccines. Among inactivated vaccines, only inactivated poliovirus and influenza vaccines do not contain aluminum salts used as adjuvants. This is true not only for U.S. licensed vaccines, but also is true around the entire world. The World Health Organization's Enhanced Program in Immunization (EPI) is highly reliant on vaccines containing aluminum adjuvants, and these vaccines have an established track record of safety extending over almost half a century.

Controversial data

By far the most controversial (scientifically entertaining) part of the workshop was presented by a French investigator, Romain Gherardi, pathologist at the Henri Mondor University in Creteil. He had published an article in The Lancet two years previously (1998;352: 347-52) describing a clinical and pathologic entity he called macrophagic myofasciitis (MMF), an unusual "new inflammatory muscle disorder of unknown cause." Based on additional work done in the two years since that publication, he presented his data at the workshop and argued that the cause of this entity is actually the aluminum in vaccines given in France.

More than 100 patients have been identified to date, and the analysis he presented was confined to the first 50 patients. The entity itself has been identified in deltoid muscle biopsies of patients with a variety of complaints, including diffuse myalgia, arthralgia, and fatigue; some but not all of these patients met the CDC definition for chronic fatigue syndrome. Biopsies revealed extensive infiltration of macrophages around, but not inside muscle fibers, with a few CD8+ T cells. Typically, there was no tissue necrosis and little evidence of muscle damage. Many of the macrophages contained para-aminosalicylic acid (PAS)-positive crystalline structures, subsequently identified as aluminum. Laboratory evidence of inflammation was variable; most patients had a normal white blood cell count and creatine phosphokinase; about half had some serum autoantibodies present. In addition, levels of certain cytokines seemed to be increased, especially interleukin (IL)-1 receptor antagonist and IL-6.

The patients were mostly middle-age adults with males and females about equally represented. All had received aluminum-containing vaccines, mostly HepB vaccine, in the biopsied deltoid muscle; a mean of 36 months had elapsed between vaccination and muscle biopsy. A high proportion of patients were health care workers, had a sports affiliation, or had traveled extensively. There was a seemingly higher than expected proportion of patients with concurrent autoimmune disease (34%). In fact, six of the 50 patients in an epidemiologic analysis had multiple sclerosis. Most patients responded to treatment with steroids and/or antibiotics.

Why only France? Dr. Gherardi related that there had been an extensive campaign there in the preceding five years to immunize adults with HepB vaccine. Also, the French typically do a deltoid biopsy whenever muscle biopsy is indicated; elsewhere, including the U.S., calf muscles such as the gastrocnemius are preferred.

Participants remained unconvinced

Most workshop participants were frankly skeptical. Many were unconvinced that MMF really represented a new entity, and all doubted that the argument that it was caused by aluminum could be sustained. In particular, his argument was faulted for a lack of controls, for there were no data on unvaccinated patients, or on patients who had been vaccinated but were asymptomatic. For that reason, many participants suggested that this was simply an epiphenomenon, or represented an epidemic of recognition, which is now feeding in France on its own publicity. To quote that most overused concluding comment, "further investigation is warranted," and indeed many additional in vitro and in vivo studies are already underway to elucidate the etiology and significance of MMF.

All the scientific uncertainties notwithstanding, most participants left the workshop reassured about the safety of aluminum adjuvants. Yet, the most relevant question - "Do we really need them?"- was never really answered.