brook et al., 1994). However, different strains of the bacillus produce seven distinct botulinum toxins (A–G). These toxins are among the most toxic compounds per body weight of agent, with an LD50 of 0.001 μg/kg in mice (for comparison, the LD50 of sarin in laboratory mice is 100 μg/kg) (USAMRIID, 1996). It is interesting to note that botulinum A toxin is successfully used to relax muscular spasms for a number of therapeutic purposes.10 The doses used are so minute that they do not produce toxic reactions, nor are they immunogenic.

Work on modifying the botulinum toxin to the nontoxic form of a toxoid began in 1924.11 Experimental work on a toxoid for use in humans was first reported in the 1930s by the Russian scientist Velikanov (Anderson and Lewis, 1981; Middlebrook and Brown, 1995). A bivalent toxoid (for serotypes A and B) was developed in the United States in the 1940s. Further research led to a pentaPublic Health (now BioPort Corporation) produced the pentavalent toxoid. valent toxoid (serotypes A–E) first produced in large lots by Parke, Davis, and Company in 1958 under contract to the U.S. Army (Anderson and Lewis, 1981). CDC submitted an Investigational New Drug application for the pentavalent toxoid in 1965 (IND 161; Rettig, 1999). In the 1970s, the Michigan Department of

Currently, the toxoid is in IND status. As described below, the toxoid has been administered to volunteers for testing purposes and to occupationally at-risk workers. Additionally, it is estimated that 8,000 U.S. troops received the toxoid during the Gulf War. Under an FDA Interim Rule (U.S. DHHS, 1990), the FDA commissioner was given the authority to waive IND requirements (e.g., informed consent) in specific military exigencies (Rettig, 1999).

The schedule for the pentavalent toxoid calls for subcutaneous injections at 0, 2, and 12 weeks, followed by annual boosters. Contraindications for administering the vaccine include alum, formaldehyde, or thimerosal sensitivities or hypersensitivity after receiving a previous dose (USAMRIID, 1996). Recent advances in molecular cloning techniques and new knowledge about the molecular mechanisms of action of the toxins have opened up avenues for new botulinum vaccine development (Middlebrook, 1995).

10  

The primary use has been to reduce muscle spasm by blocking the release of acetylcholine at the neuromuscular junction. This is used in the treatment of strabismus, hemifacial spasm, cervical dystonia, and other spastic disorders (Cardoso and Jankovic, 1995; Tsui, 1996). Transient local muscle weakness can occur; however, no hypersensitivity reactions have been reported (Tsui, 1996). Systemic effects such as fever, malaise, fatigue, and flulike symptoms have been observed but in one double-blind study occurred less frequently than when placebo was given (Tsui, 1996).

11  

A toxoid is a modified bacterial toxin that is made nontoxic but has the capacity to stimulate the formation of antitoxin antibodies (Fauci et al., 1998).



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