efficacy, several investigators noted a possible increased incidence of disease in the immediate postimmunization period (less than 7 days) (Black et al., 1988; Harrison et al., 1988; Osterholm et al., 1988; Shapiro et al., 1988).

In the 1980s, several groups of investigators developed the first Hib polysaccharide-protein conjugate vaccines. Enhancement of the immunogenicity of carbohydrate antigens by chemical conjugation with proteins had been reported in 1929 by Avery and Goebel, but the idea had not been previously applied to the development of vaccines for human use. The Hib conjugate vaccines prepared by Schneerson et al. (1980), Gordon (1984), and Anderson (1983) showed enhanced immunogenicity and T-cell-dependent characteristics, that is, responses in immature animals, booster responses, predominance of immunoglobulin G (IgG) antibodies, and priming by prior carrier immunization.

A series of Hib conjugate vaccines was developed, tested, and licensed in the late 1980s. These vaccines differ in the molecular size of the Hib polysaccharide, the protein used as the carrier, and the methods used to link the polysaccharide to the protein (Table 9-1). Thus, in consideration of the side effects of Hib conjugate vaccines, it is plausible that variations in the type or frequency of adverse effects may occur because of differences in the polysaccharide or protein components of the vaccines.

Routine immunization of infants with Hib conjugate vaccine in a multiple-dose schedule is now recommended in the United States (American Academy of Pediatrics, Committee on Infectious Diseases, 1991b; Centers for Disease Control, 1991a). Because of the need to provide protective immunity during the high-risk period of infancy and for parental convenience, Hib conjugate vaccines are given simultaneously with diphtheria and tetanus toxoids and pertussis vaccine (DPT) and polio vaccines. The efficacies of these schedules on the basis of the results of prelicensure trials were estimated to be greater than 90 percent for PRP-outer membrane protein vaccine (PRP-OMP) in Navajo infants when given at 2 and 4 months of age (Santosham et al., 1992) and 100 percent after three doses of oligosaccharide conjugate Hib (HbOC) vaccine given at 2, 4, and 6 months of age (Black et al., 1992a). A new Hib conjugate vaccine, PRP conjugated to tetanus toxoid (PRP-T), was licensed on March 30, 1993 (Centers for Disease Control and Prevention, 1993). The immunogenicity of this vaccine in infants immunized at ages 2, 4, and 6 months is similar to that of previously licensed Hib conjugate vaccines (Decker et al., 1992). Although controlled trials of the efficacy of PRP-T in the United States had to be terminated because of licensure of other conjugate vaccines, no cases of invasive disease were detected in approximately 100,000 infants given two or more doses in these and other studies (Fritzell and Plotkin, 1992; Greenberg et al., 1991), and a controlled trial in the Oxford region of the United King-

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