Antibody responses to Haemophilus influenzae type b polysaccharide vaccine in relation to Km(1) and G2m(23) immunoglobulin allotypes.

The antibody responses of children immunized with Haemophilus influenzae type b polysaccharide vaccine were examined in relation to the absence or presence of the Km(1) or G2m(23) immunoglobulin allotype. Ninety-seven children, 12-83 months of age, were immunized. Sera were obtained before immunization and two months later. Total serum antibody to the type b capsule was detected by a radioactive antigen-binding assay. IgG and IgM antibody responses were measured by enzyme-linked immunosorbent assay. Antibody responses to the type b capsule were more than threefold higher in blacks with the Km(1) immunoglobulin allotype compared with those in blacks lacking this allotype (P less than .02). The isotype affected was IgG (P less than .01) and not IgM. Serum concentrations of IgG2, but not of IgG1, also were higher in blacks with Km(1) (P less than .003). In whites there were no significant differences in the total or IgG-specific antibody responses to the type b capsule in relation to the Km(1) or G2m(23) allotype.

Haemophilus influenzae type b disease in an Amish population: studies of the effects of genetic factors, immunization, and rifampin prophylaxis on the course of an outbreak.

In 1982, an outbreak of Haemophilus influenzae type b disease occurred in a 379-member Amish community. In an attempt to control the outbreak after the occurrence of the second case of disease, we investigated the combination of (1) rifampin chemoprophylaxis of all carriers of H influenzae type b and their household contacts from 1 month to 5 years of age and (2) H influenzae type b polysaccharide vaccine immunoprophylaxis of all community members 12 months of age and older. Despite our intervention, two additional cases of bacteremic H influenzae type b disease occurred in the ensuing 5 months, one in a 22-month-old infant who had been immunized at 19 months of age and the other in a child who had not been immunized because she was younger than 12 months of age. The outbreak ended following rifampin prophylaxis of all community members younger than 15 years of age. All of the children with disease were genetically related to one another, and three of the four were inbred. However, analysis of their coancestry revealed that neither the average level of kinship nor the average inbreeding level of the affected children differed significantly from those of the other children in the community. Furthermore, none of the four children with disease shared a human leukocyte antigen haplotype. Our observations suggest that inbreeding was not a risk factor in this community.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of rifampin chemoprophylaxis on carriage eradication and new acquisition of Haemophilus influenzae type b in contacts.

We conducted a multicenter trial designed to assess the efficacy of three different drug regimens on eradication of Haemophilus influenzae type b (HIB) from the nasopharynx of household contacts of patients with invasive type b Haemophilus disease. The drug regimens studied were rifampin, 20 mg/kg, once daily for four days; rifampin, 10 mg/kg, twice a day for four days; and placebo, once daily for four days. Shortly after admission of the index patient to the hospital, 26% of 492 household contacts were found to be colonized with HIB. Both rifampin regimens eradicated carriage significantly better than placebo at 10 and 30 days (P = .001). However, among contacts whose cultures were initially negative, new acquisition of the organism occurred infrequently in this 30-day follow-up period regardless of the drug or placebo regimen prescribed. We also measured the concentration of anticapsular antibody in sera obtained from contacts younger than 6 years of age. Samples were obtained soon after admission of the index patient to the hospital and 30 days later. Several carriers younger than 2 years of age had low concentrations of antibody in both specimens. In contrast, nearly all carriers 2 to 5 years of age had high concentrations of antibody even in the first sample. Children who were not carriers usually had low antibody concentrations which did not increase during the period of observation. Our results suggest that most intrafamilial spread of HIB occurs prior to hospitalization of the index patient and stimulates immunity in contacts older than 2 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Ceftriaxone in the treatment of infections caused by Staphylococcus aureus in children.

Ceftriaxone is a new parenteral cephalosporin with a prolonged half-life and an expanded Gram-negative spectrum. Before it can be used as a single agent for infections of unknown etiology, its efficacy in treating infections caused by Gram-positive organisms, particularly Staphylococcus aureus, must be proven. Ceftriaxone was administered to 12 children for treatment of infections due to S. aureus alone or in the presence of other organisms. Sites of infection included soft tissue, respiratory tract, bone and joint. Patients received ceftriaxone at 68 to 100 mg/kg/day in two doses for 3 to 20 days. Clinical and bacteriologic responses were satisfactory in all patients. One patient experienced abdominal pain during infusion and another developed a skin rash. Five patients had platelet counts of 500,000/mm3 or greater; four had an eosinophil count of 7% or greater and one patient had transient neutropenia. These abnormalities resolved during or after therapy. Ceftriaxone was a safe and effective single antibiotic for the treatment of infections caused by S. aureus in children.

Response to immunization with Haemophilus influenzae type b polysaccharide-pertussis vaccine and risk of Haemophilus meningitis in children with the Km(1) immunoglobulin allotype.

In experimental animals, immune responses to certain antigens are regulated by immunoglobulin allotype-linked genes. In an effort to detect such genes in humans, we examined the antibody responses of 74 healthy children with different Km(1) or Gm(23) allotypes to a Haemophilus influenzae type b vaccine (type b polysaccharide capsule-pertussis vaccine). The anticapsular antibody responses of black or white children with the Km(1) allotype were 4.6- to 9.5-fold higher than those of children who lacked this determinant (P less than 0.004). No significant differences were found in antibody response with respect to the Gm(23) allotype. The frequencies of Km(1) and Gm(23) also were examined in 170 patients with Haemophilus meningitis, 71 patients with epiglottitis, and 173 control children. Km(1) was detected less frequently in black patients with meningitis (38%) than in those with epiglottitis (81%, P less than 0.002) or in controls (66%, P less than 0.0007). The relative risk of meningitis thus was 3.2-fold lower among black children with the Km(1) allotype than in those who lacked this allotype (odds ratio = 0.3, 95% confidence interval 0.2 to 0.6). However, the risk of meningitis was not decreased in white children with the Km(1) allotype (odds ratio = 1.0). There were no significant differences in the frequency of Gm(23) among the patient groups and controls. The Km(1) allotype but not the Gm(23) thus defines a subpopulation of children of both races who are high responders to this vaccine, and black children but not white children with the Km(1) allotype are at decreased risk of developing Haemophilus meningitis. These data indicate that in blacks, genes associated with Km(1) may affect immune response to a prototype type b Haemophilus vaccine, and perhaps interact with another factor related to race to affect susceptibility to Haemophilus meningitis.

Immunogenicity of Haemophilus influenzae type b polysaccharide--diphtheria toxoid conjugate vaccine in adults.

The capsular polysaccharide of Haemophilus influenzae type b is a poor immunogen in human infants. In an attempt to enhance immunogenicity, this polysaccharide was covalently coupled to diphtheria toxoid and the conjugate tested as a vaccine in adult volunteers. Two injections of PRP-D vaccine were given, separated by one month. The anti-PRP antibody responses in this group were compared with those in a group receiving a comparable dose (20 micrograms) of conventional PRP vaccine. Both vaccines were well tolerated. A single injection of PRP-D was significantly more immunogenic than PRP, eliciting higher serum concentrations of total anti-PRP antibody 1 month later (geo means of 248 and 62 micrograms/ml, respectively; P less than 0.001). In addition, higher concentrations of IgG anti-PRP antibody were observed in the PRP-D group (P less than 0.001). One month after reinjection of vaccine, subjects receiving PRP-D showed a small but significant decline in total antibody (P = 0.03), whereas the serum antibody concentrations in the group that received PRP remained unchanged. At 12 months, the antibody concentrations of the two groups were not significantly different. Bactericidal activity and passive protection activity (infant rat model) were tested in pooled sera from the three highest and three lowest responders in each vaccine group; both PRP and PRP-D vaccines induced biologically active anti-PRP antibody. Thus PRP-D was found to elicit biologically active serum antibody and to be more immunogenic in adults than PRP vaccine; however, the duration of higher concentrations of antibody was transient.

Interactive effect of genes associated with immunoglobulin allotypes and HLA specificities on susceptibility to Haemophilus influenzae disease.

Genes associated with immunoglobulin (Ig) allotype determinants are important in regulation of immune responses to bacterial polysaccharides. Furthermore, loci associated with Ig allotypes have been reported to interact with those associated with the major histocompatibility complex and affect susceptibility to certain diseases. In the present study we determined the frequencies of certain Gm phenotypes in patients with Haemophilus meningitis or epiglottitis and in controls. HLA-A, -B and -DR specificities had previously been determined in the majority of these subjects. Although no Ig phenotype was associated with increased or decreased relative risk of disease, the frequencies of several combinations of HLA specificities and Ig phenotypes were significantly different from those of controls. Thus, for subjects with the Gm phenotype (1, 3, 17; 23; 5, 13, 21), the risk of Haemophilus meningitis or epiglottitis was lower in individuals with HLA-B5 than in those without this specificity (odds ratio less than 0.1, P less than 0.004). In contrast, for subjects with the closely related Gm phenotype differing only by the absence of Gm(23), (1, 3, 17; ; 5, 13, 21), the risk of disease was higher in those with HLA-DR3 than in individuals who lacked DR3 (odds ratio = 11.0, P = 0.02). Although the present data require confirmation in an independent sample, they suggest that complex interactions between genes at two independent loci controlling HLA and Ig allotypes, respectively, may affect susceptibility to Haemophilus disease.

Histocompatibility leukocyte antigen and erythrocyte MNSs specificities in patients with meningitis or epiglottitis due to Haemophilus influenzae type b.

The frequencies of erythrocyte MNSs antigens and certain histocompatibility leukocyte antigen (HLA) specificities (HLA-A, HLA-B, and HLA-DR) were determined in white patients with meningitis or epiglottitis due to Haemophilus influenzae type b and in controls. The frequency of the erythrocyte MNSs genotype was significantly lower among patients with meningitis than among those with epiglottitis (P = 0.03); this observation confirms a trend observed previously. However, the frequencies of the HLA specificities did not differ significantly in the three groups studied; this result fails to confirm previous reports of disease associations with several HLA-A and HLA-B specificities. Although susceptibility to different clinical manifestations of haemophilus disease may be influenced by genetic factors, our studies indicate that the major loci conferring susceptibility are not in linkage disequilibrium with specificities in the major histocompatibility complex.

Rifampin alone and in combination with trimethoprim in chemoprophylaxis for infections due to Haemophilus influenzae type b.

The efficacy of rifampin in eradicating Haemophilus influenzae type b from the pharynx of colonized individuals was assessed for 1,467 close contacts of 291 children hospitalized with invasive infections due to H. influenzae type b. Twenty-six percent of all contacts were carrying H. influenzae type b in the pharynx, and 52% of contacts younger than age five had throat cultures positive for this organism. Four different regimens of rifampin were studied and compared with placebo for efficacy in eradication of carriage of H. influenzae type b. The most effective dosage was 20 mg of rifampin/kg given once daily for four days. This schedule was associated with eradication of carriage in 96.2% of 52 colonized, compliant contacts. Carriage of H. influenzae type b was eradicated in 90.9% of the 22 colonized contacts who were younger than age five. Significantly lower rates of carriage eradication were seen with other regimens of rifampin. Potential problems associated with widespread rifampin usage are reviewed.