purified anthrax protective antigen found adverse effects from one of the adjuvant combinations containing squalene; other adjuvants containing squalene did not elicit adverse reactions. Tests of an HIV candidate vaccine with MF59 found no embryotoxic or teratogenic effects in dogs or rabbits (Ott et al., 1995).

Clinical studies of MF59 and other squalene-containing adjuvants have been conducted with candidate malaria, HSV (herpes simplex virus), HIV (human immunodeficiency virus), and influenza vaccines (Ott et al., 1995; GAO, 1999a). Study populations for the clinical trials have included adults, elderly, and children and infants (Ott et al., 1995).

HIV Vaccine Trials

Keefer and colleagues (1996) investigated the safety and immunogenicity of a candidate HIV-1 vaccine in combination with MF59, with or without an additional immune modulator, MTP–PE (muramyl tripeptide linked covalently with dipalmitoyl phosphatidylethanolamine). Vaccination with the candidate vaccine Env 2-3 in MTP–PE/MF59 was associated with significant adverse effects; severe, though short-lived, systemic and/or local reactions occurred in 15 of 30 vaccinees. In contrast, Env 2-3 in MF59 without MTP–PE was relatively well tolerated; severe local and/or systemic reactions occurred in only 2 of 18 subjects. There were no severe reactions in the eight subjects that received MF59 alone.

Graham and colleagues (1996) evaluated the safety and immunogenicity of another candidate vaccine for HIV, the recombinant glycoprotein 120, formulated with MF59 with or without MTP–PE. Vaccines that contained MTP–PE caused a greater number of moderate or severe local and systemic reactions (of 16 participants, 4 had local reactions and 13 had systemic reactions) than did vaccine formulated with MF59 alone. Of 16 vaccinees, 7 had local reactions and 0 had systemic reactions.

The National Institute of Allergy and Infectious Diseases (NIAID)-sponsored AIDS Vaccine Evaluation Group examined safety data from 1,398 HIV-negative, healthy volunteers who were enrolled in 25 multicenter, randomized double-blind studies evaluating 11 HIV candidate vaccines (Keefer et al., 1996). The study examined the adverse effects of a number of adjuvants, including MF59 and MF59 formulated with the biological response modifier MTP–PE. MTP–PE was associated with moderate to severe local reactions as well as with self-limited severe systemic reactions that resolved within 2–3 days. The same vaccines in the MF59 emulsion alone were well tolerated (Keefer et al., 1996).

Influenza Vaccine Trials

The safety and efficacy of MF59 have been evaluated in pilot studies (Keitel et al., 1993) and clinical trials (Martin, 1997; Menegon et al., 1999; Minutello et al., 1999). A study by Martin (1997) assembled data from eight randomized controlled clinical trials over four influenza seasons; 984 elderly

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