formaldehyde or preservative in the toxoid preparation, contaminant proteins in the toxoid preparation, toxin that has not been inactivated by formaldehyde, and/or the adjuvant.

Studies in veterinary use. Botulinum toxoids type C and D. Animal botulism is caused principally by the type C and D neurotoxins. In veterinary use, vaccination of mink and ferrets (Pranter, 1976; Shen et al., 1981), chickens (Dohms et al., 1982; Kurazono et al., 1985), pheasants (Kurazono et al., 1985), and cattle (Tammemagi and Grant, 1967) has been reported using either monovalent type C toxoid or bivalent types C and D. These studies did not mention adverse effects from vaccination. In the study using type C toxoid in chicks (Dohms et al., 1982), survivors of the toxin challenge showed no lesions at the site of vaccination. In addition, Davidson (1976) reviewed the use of types C and D toxoids for veterinary purposes and did not mention adverse effects due to vaccination. The primary purpose of most of the studies was to evaluate the effectiveness of the vaccine against challenge with the botulinum neurotoxin, not to evaluate adverse effects. Most of the studies monitored animals for 1–2 months.

Botulinum toxoid type B in veterinary practice and laboratory animals. Shaker foal syndrome is a neuromuscular condition affecting 2- to 8-week-old foals. Administering type B botulinum toxoid can mimic the symptoms of shaker foal syndrome. Swelling at the injection site has been reported in four horses administered two doses of type B botulinum toxoid (Thomas et al., 1988). These swellings were hard and approximately 75 cm2 in area. The report did not state if the swelling occurred with the first, second, or both doses of the toxoid.

Studies in laboratory animals. Studies with botulinum toxoids have been done in guinea pigs, rabbits, and mice with type E (Kondo et al., 1969), type A (Gendon, 1958), and pentavalent types A–E toxoid (Cardella, 1964); in mice with type F toxoid (Mikhailova, 1966); and in guinea pigs with types C and D toxoid (Mathews, 1976). In none of these studies did the authors mention adverse effects, which may indicate that no adverse effects occurred, that adverse events were not monitored, or that the adverse events were not sufficiently severe to warrant termination of the experiment.

Studies in guinea pigs suggest that skin-sensitizing anaphylactic antibodies may be produced in response to the administration of a combination of type B botulinum toxoid with the complex typhoid antigen (Yefremova, 1980). Such skin-sensitizing antibodies in the guinea pig are associated with immediate hypersensitivity reactions and respiratory allergy. Effects of administration of type B toxoid alone were not investigated in this study.

Recombinant DNA methods have been used to generate fragments of the botulinum neurotoxins, in hopes of developing a molecule without neurotoxicity but able to provoke an immune response and protect against botulinum neurotoxin activity. Such fragments of types A, B, and C botulinum neurotoxin have been generated and tested for toxicity and immunogenicity in mice (Middle-



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