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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality
immune complexes form locally in the walls of small arteries (Edsall et al., 1967; Eisen et al., 1963; Facktor et al., 1973). In rare cases, it is possible that the immune complexes may form in the circulation, deposit in tissues, and activate complement. This would result in the clinical syndrome of serum sickness. These patients may develop glomerulonephritis, arthritis, and vasculitis. However, some investigators have been unable to confirm a consistent correlation between more severe local reactions and high antibody levels (Holden and Strang, 1965; Jones et al., 1985; White et al., 1973), and thus, it is likely that other factors such as toxoid variables, adjuvants, dose, and host factors may also play a role in the development of severe local reactions.
Routine immunization with tetanus toxoid also induces a cellular immune response, and intradermal skin testing with tetanus toxoid frequently is used as a screen for anergy (Gordon et al., 1983; Grabenstein, 1990; Steele et al., 1976). The absence of a delayed-type hypersensitivity response does not imply a lack of protective immunity, and conversely, a positive response does not appear to correlate with clinically important hypersensitivity reactions to the toxoid (Eisen et al., 1963; Facktor et al., 1973; Gold, 1941; Vellayappan and Lee, 1976).
In the preimmunization era, many people acquired immunity to diphtheria (and a negative Schick test) presumably by asymptomatic colonization. Also, protective immunity was observed in young infants, most likely on the basis of the presence of transplacentally acquired antibody (Schick, 1913).
Diphtheria toxoid adsorbed with aluminum hydroxide or phosphate was shown to be more immunogenic and to produce fewer local reactions than fluid toxoid. The minimum schedule for children was found to be three doses, with the first two doses spaced by 1-2 months and the third dose given 6-12 months later. Booster doses were found to be necessary, particularly in countries where widespread immunization markedly decreased the opportunity for asymptomatic colonization (Bjorkholm et al., 1986; Christenson and Bottiger, 1986; James et al., 1951; Karzon and Edwards, 1988; Rappouli et al., 1988). To maintain protective levels of antitoxin antibody against diphtheria, recall immunization is suggested in older children and adults at 10-year intervals.
Early studies of the immune response to immunization against diphtheria revealed that some immune individuals responded to a Schick test with immediate hypersensitivity reactions (wheal and erythema within minutes) or delayed-type hypersensitivity reactions that were maximal at 24-72 hours (Zingher and Park, 1923). An important consequence of this observation