on eukaryotic messenger RNA. A single molecule of fragment A can kill a cell. Fragment B ("binding") is responsible for the recognition of receptors on mammalian cells and the translocation of fragment A into cells (Uchida, 1986). Protective human antibodies against diphtheria are directed against fragment B (Mortimer, 1988). The protective role of antisera against the toxin was documented by Behring in the late nineteenth century (Holmes, 1940), and the use of diphtheria antiserum raised in horses to treat human diphtheria was introduced a few years later. Active immunization with inactivated toxin in experimental animals was adapted to immunization of humans.

Early in the history of immunization against diphtheria, active toxin and antitoxin (prepared in horses) were administered as a mixture. In several reports, fatalities caused by the toxic effects of inadequately neutralized diphtheria toxin occurred in children given these mixtures (Dittmann, 1981b; Wilson, 1967). Following the introduction of toxin neutralization by chemical means (formalin), one report of incomplete detoxification appeared. In Kyoto, Japan, in 1948, 68 of 606 children died following inoculation with a formalin-detoxified vaccine. Free toxin was detected in one batch of the vaccine (Dittmann, 1981b). Currently licensed toxoids produced in the United States are now prepared and tested by procedures specified in the Code of Federal Regulations, and no cases of toxin-related disease have been reported since 1948.

Because of the severity of clinical diphtheria and the early recognition that protection was safely induced by immunization with diphtheria toxoid, controlled clinical trials of the efficacy of diphtheria toxoid were never performed. Early in the history of immunization against diphtheria, Schick (1913) introduced a test that correlated with protective immunity, thus making it possible to study both naturally acquired and toxoid-induced immunity. This test consists of the intradermal injection of a small amount of purified toxin. In nonimmune individuals who lack circulating antitoxin, a red, slightly hemorrhagic area appears at the injection site within 48 hours. Individuals with protective levels of antitoxin antibody (>0.01 U/ml) have no local reaction. On the basis of the correlation of a negative Schick test with protective immunity and a correlation between negative Schick test results and a serum antitoxin titer of 0.01 to 0.02 U/ml, one or both of these tests have been used to measure the efficacy of diphtheria immunization protocols that utilize various doses and administration schedules.

In the United States, children receive vaccines according to schedules determined by the American Academy of Pediatrics and the Advisory Committee on Immunization Practices. These groups recommend that diphtheria and tetanus toxoids and pertussis vaccine (DPT) be given at ages 2, 4, and 6 months, between ages 15 and 18 months, and between ages 4 and 6 years. The acellular pertussis-containing (DTaP) preparation can be substituted for



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