CDC presented to the committee a brief review of issues related to aluminum-containing adjuvants and adverse events (CDC, 2002l). Aluminum is one of the most abundant elements on earth, and humans are routinely exposed to it through sources such as drinking water, medications (e.g., antacids), and deodorants. Little is known about the toxicology of injected aluminum, and human studies of the clearance of aluminum have been limited to patients with chronic renal insufficiency.

Aluminum compounds are used as adjuvants in some vaccines to enhance the immunogenicity of the product. AVA uses aluminum hydroxide as an adjuvant, and several other vaccines routinely administered to children and adults also use adjuvants containing aluminum. These vaccines include the diphtheria and tetanus toxoids and pertussis vaccine (DTP), other vaccines containing tetanus toxoids, and hepatitis B vaccine. While vaccine adjuvants containing aluminum have been used for many years, they have been associated with some local adverse events, such as erythema, subcutaneous nodules, skin allergy, and skin inflammation at the injection site. Adverse events of this type also occur in persons who receive AVA, but studies have not been done to establish whether the adverse events observed following receipt of AVA are related to the adjuvant.

Recently, it has been suggested that aluminum-containing vaccine adjuvants might be associated with a condition that has been labeled macrophagic myofasciitis (MMF) (Gherardi et al., 1998, 2001). The symptoms attributed to this condition include myalgias, arthralgias, muscle weakness or tenderness, and fatigue. Aluminum has been found in tissue biopsies of persons considered to have the condition, but tissue biopsies from suitable control groups have not been tested. Thus, it remains uncertain whether the presence of aluminum in tissue biopsies of persons said to have MMF is a sign of pathology or only a coincidental finding.

CDC (2002l) listed five possible research questions that might be investigated:

1. Are subcutaneous nodules following AVA vaccination caused by subcutaneous accumulation of aluminum hydroxide adjuvant?

2. Is the gender differential in the occurrence of adverse events observed following AVA vaccination associated with impaired local clearance of aluminum hydroxide adjuvant?

3. Are individuals (particularly women) with iron deficiency anemia more prone to develop injection-site adverse events, including subcutaneous nodules, following AVA vaccination?

4. Are individuals (particularly women) with iron deficiency anemia more prone to develop systemic adverse events following AVA vaccination?

5. Is macrophagic myofasciitis (MMF) a condition associated with AVA?

CDC assigned this topic a lower priority than the other proposed studies and noted in the materials provided to the committee that no study proposals or protocols had been developed.

The committee acknowledges that there are concerns that the aluminum adjuvant in AVA might contribute to certain types of adverse events or adverse events in certain people. However, a summary of a May 2000 workshop on aluminum in vaccines (Eickhoff and Myers, 2002) indicates that the pervasiveness of aluminum in the environment and the limited understanding of the toxicology and kinetics of injected aluminum adjuvants pose serious scientific and practical challenges to efforts to investigate health effects that might be associated with a specific source of exposure, such as AVA. Furthermore, the preliminary nature of the evidence concerning MMF suggests that it is premature to investigate whether re-

Front Matter (R1-R20)

Executive Summary (1-17)

1 Introduction (18-22)

2 Background (23-32)

3 The CDC Anthrax Vaccine Research Plan (33-42)

4 Proposed Studies on the Efficacy of the Anthrax Vaccine (43-55)

5 Proposed Studies on the Safety of the Anthrax Vaccine (56-81)

6 Proposed Studies on the Acceptability of the Anthrax Vaccine (82-90)

7 Summary Assessment of the CDC Anthrax Vaccine Research Plan (91-100)

Appendix A: Biographical Sketches (101-104)

Appendix B: Information-Gathering Meeting Agendas (105-112)

Appendix C: CDC Anthrax Vaccine Safety and Efficacy Research Plan (113-136)

Appendix D: Food and Drug Administration Final Rule: New Drug and Biological Drug Products ; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible (137-148)

Appendix E: Department of Defense Memorandum: Reintroduction of the Anthrax Vaccine Immunization Program (149-152)

Appendix F: Institute of Medicine: CDC Anthrax Vaccine & Safety Efficacy Research Program: Interim Report--Findings and Recommendations (153-154)

Appendix G: Institute of Medicine: The Anthrax Vaccine: Is It Safe? Does It Work?--Findings and Recommendations (155-160)