Persistence of antibody and booster responses to reimmunization with Haemophilus influenzae type b polysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children initially immunized at 15 to 24 months of age

To evaluate the persistence of antibody after Haemophilus influenzae type b polysaccharide vaccine (PRP) and H influenzae type b polysaccharide diphtheria toxoid conjugate vaccine (PRP-D), a group of 141 infants initially immunized between 15 and 24 months of age were studied 1 year later. One month after immunization with PRP, the man anti-PRP antibody level was 0.27 microgram/mL and 1 year later was 0.29 microgram/mL (not significant). In the group immunized with PRP-D, the levels were 1.34 micrograms/mL and 1.20 micrograms/mL (not significant), respectively. To evaluate immunogenicity and safety of a booster immunization 1 year after initial vaccination, subjects were randomly assigned to receive saline, PRP, or PRP-D. In addition, 73 age-matched previously unimmunized subjects were vaccinated with PRP or PRP-D. In all groups, adverse reactions were minor and resolved by 48 hours. Subjects receiving booster immunization with PRP or PRP-D had significantly greater antibody responses than children of the same age receiving their first dose of vaccine. The highest antibody levels were achieved in children initially immunized with PRP-D, regardless of whether the booster vaccine was PRP (112.8 micrograms/mL) or PRP-D (122.0 micrograms/mL) (not significant). Antibody levels after booster vaccine were significantly lower in those initially given PRP compared with those initially given PRP-D but significantly higher than in age-matched previously unimmunized control subjects (PRP booster 3.16 micrograms/mL vs control of 0.62 microgram/mL [P less than .05]; PRP-D booster 12.31 micrograms/mL vs control 2.31 micrograms/mL [P less than .01]).     

Safety and immunogenicity of Haemophilus influenzae type b polysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children 15 to 24 months of age

To evaluate the safety and immunogenicity of the Haemophilus influenzae type b polysaccharide vaccine, PRP, and a new polysaccharide-diphtheria toxoid conjugate vaccine, PRP-D, a collaborative study was carried out in six centers in five states. Subjects were 585 infants 15 to 24 months of age. They were randomly assigned to receive a single dose of PRP or PRP-D vaccine. There were no significant differences in the rate of adverse reactions between the two vaccine groups. Minor local reactions occurred in 10.3% of PRP and 12.5% of PRP-D recipients, and fever in 27.4% of PRP and 23.8% of PRP-D recipients. All reactions resolved within 48 hours. Serum samples were obtained just before vaccination and after 1 month. Prevaccination antibody levels were similar for the PRP (0.035 micrograms/mL) and PRP-D (0.027 micrograms/mL) groups, with no differences in levels by age, sex, race, vaccine lot, or study site. Both groups had significant rises in geometric mean levels, but this difference was significantly greater for PRP-D (2.166 micrograms/mL) than for PRP (0.154 micrograms/mL). In addition, the percentage of responders as determined by three definitions (twofold titer rise, greater than 0.15 micrograms/mL, and greater than 1.0 micrograms/mL) was also significantly greater for PRP-D than PRP. In contrast to a marked age-related immunogenicity to PRP (P less than 0.001), there was no significant variation in immune response to PRP-D by age. PRP-D conjugate vaccine appears to be as safe and significantly more immunogenic than PRP vaccine for children vaccinated at 15 to 24 months of age.     

Reimmunization of children immunized at 18 months of age with Haemophilus influenzae type b vaccine

We studied the response to reimmunization at 36 months of age with Haemophilus influenzae type b (Hib) polyribosylribitol phosphate (PRP) capsular polysaccharide vaccine. Children enrolled in the study had previously received PRP or PRP plus diphtheria and tetanus toxoids with pertussis vaccine at 18 months of age. A control group of children, who received a first dose at 36 months of age, was also studied. Ninety-five percent of children receiving a second dose of vaccine had a postimmunization anti-capsular antibody level of greater than or equal to 1 microgram/mL. In comparison, 70% of 36-month-old children who received their first dose of PRP had a postimmunization level greater than or equal to 1 microgram/mL (P = 0.09). The geometric mean titer at 37 months of age was 8.64 micrograms/mL in children who had received two doses of PRP vaccine, compared with 2.19 micrograms/mL in the group who received only one dose of PRP at 36 months of age (P = 0.04). We conclude that infants immunized at 17 to 19 months of age with PRP had an excellent immunologic response to reimmunization at 36 months of age.     

Immunogenicity of the Haemophilus influenzae type b capsular polysaccharide conjugate vaccine in children after systemic Haemophilus influenzae type b infections

We immunized 24 patients (mean age 15.2 +/- 9.3 months) with polyribosylribitol phosphate-diphtheria toxoid conjugate vaccine (PRP-D) 2 months after a systemic Haemophilus influenzae type b infection. Children less than 24 months of age were immunized twice. Serum was obtained for antibody to PRP before and 1 or 2 months after immunization. Three of five children greater than 24 months of age and three of six children 18 to 24 months of age developed greater than 1 microgram/ml of antibody after immunization, and geometric mean postimmunization levels were significantly greater than preimmunization levels for both groups. However, two children who failed to respond to conventional PRP vaccine did not respond as expected to one dose of PRP-D. For children 7 to 17 months of age, the geometric mean PRP antibody levels increased as follows: preimmunization, 0.05 micrograms/ml; after the first dose, 0.28 micrograms/ml (p = 0.003); and after the second dose, 3.39 micrograms/ml (p = 0.001). Of 13 children, 10 developed antibody values greater than 1.0 micrograms/ml. PRP conjugate vaccines are immunogenic in young children who have not developed protective PRP antibody levels after a systemic H. Influenzae type b infection.     

Vaccination of 18-month-old children with conjugated polyribosyl ribitol phosphate stimulates production of functional antibody to Haemophilus influenzae type b

Eighteen-month-old children were immunized with polyribosyl ribitol phosphate (PRP) of Haemophilus influenzae type b or with PRP that had been conjugated to diphtheria toxoid. Conjugated vaccine stimulated significant mean increases in antibody titer as measured by radioimmunoassay and bactericidal effect, as well as a modest increase in opsonizing activity. In contrast unconjugated vaccine caused lesser albeit significant rises in antibody titer, but a negligible antibacterial effect. These results suggest that vaccinating infants with conjugated PRP is more likely to stimulate production of antibodies that are protective against systemic infection caused by H. influenzae type b than vaccinating with unconjugated PRP.     

Immunization of children with sickle cell disease with Haemophilus influenzae type b polysaccharide vaccine

There are limited data concerning safety and immunogenicity of Haemophilus influenzae type b polysaccharide vaccine in children with sickle cell disease. Ninety-eight patients with sickle cell disease (65 with SS phenotype, 23 with SC phenotype, and 10 with S beta-thalassemia) 1.5 to 20 years of age were given 25 micrograms of vaccine subcutaneously. The vaccine was well tolerated; mild side effects were observed in 6 of 98 (6.1%) children. In addition, one patient with a recent vasoocclusive crisis was hospitalized because of fever and vasoocclusive crisis 8 hours after vaccination. Prevaccination anticapsular antibody concentrations (by radioimmunoassay) were less than 0.15 microgram/mL in 7 of 11 children 18 to 24 months of age (geometric mean 0.17 microgram/mL), in 10 of 25 children 2 to 5 years of age (geometric mean 0.36 microgram/mL), and in 3 of 50 patients 6 to 20 years of age (geometric mean 1.03 microgram/mL). Inadequate response (1- to 2-month postvaccination antibody level less than 1 microgram/mL) was found in 3 of 5 children 18 to 24 months of age (geometric mean 1.74 microgram/mL), in 8 of 21 children 2 to 5 years of age (geometric mean 2.20 micrograms/mL), and in 2 of 49 patients 6 to 20 years of age (geometric mean 18.03 micrograms/mL). Six months after vaccination, greater than 1 microgram/mL of antibody was present in the 2 children 6 to 20 years of age with inadequate response but not in the 7 children 2 to 5 years of age with inadequate response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Excretion of Haemophilus influenzae type b polysaccharide antigen in urine of healthy nasopharyngeal carriers

We measured concentrations of Haemophilus influenzae type b (Hib) polysaccharide antigen by ELISA in urine samples from 81 healthy North American children with positive or negative throat cultures for Hib, to investigate the possibility that asymptomatic carriers may have antigenuria. For comparison, we determined the concentrations of Hib polysaccharide antigen in urine samples from 56 patients with proven Haemophilus disease, including 13 children with lower respiratory infections who resided in developing countries. Among the healthy children, antigen was detected in the urine of seven of 19 (37%) carriers of Hib compared with one of 62 (2%) children with negative throat cultures (p less than 0.001). Among the patients with invasive Haemophilus infections, 93% had antigen detected. Although there was overlap in the concentrations of antigen in the positive urines from the asymptomatic carriers and those of the ill patients, the concentrations of the ill patients were higher than those of the carriers. The respective geometric means of the positive patients were: American patients with meningitis, 42.5 ng/mL (range 1.7-9800 ng/mL); American patients with infections not involving the CNS, 5.8 ng/mL (range: 1.0-96 ng/mL); patients from developing countries with lower respiratory infections, 29.6 ng/mL (range: 0.9-5290), and American asymptomatic carriers, 1.9 ng/mL (range: 0.6-16.7 ng/mL). Thus, antigenuria is present in a high proportion of healthy children with positive throat cultures for Hib, and the antigen concentrations of the carriers overlap those of ill patients. These results suggest that either mucosal colonization itself is sufficient to produce antigen-uria, or asymptomatic carriers may be experiencing asymptomatic invasive Hib infection.     

Safety and immunogenicity of Haemophilus influenzae type b-polysaccharide diphtheria toxoid conjugate vaccine in infants 9 to 15 months of age

Sixty 9- to 15-month-old infants were randomly assigned to receive two doses, 1 month apart, of a Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) or PRP vaccine, each containing 20 micrograms PRP. There were no significant local or systemic reactions. After one dose of PRP-D, 93% of the subjects attained levels of greater than or equal to 0.15 microgram/ml and 59% achieved greater than or equal to 1 microgram/ml antibody protein. These percentages rose to 100% and 86%, respectively, after the second dose, at which time the geometric mean titer of anti-PRP antibody was 4.8 micrograms/ml. IgG anti-PRP levels were 4.3 times higher than IgM. The proportion of IgG to IgM antibody induced by PRP-D increased with age. After two doses, 33% of the PRP recipients responded with a level of greater than or equal to 0.15 microgram/ml and only 19% responded to a level of greater than or equal to 1.0 microgram/ml. One year later, all of the PRP-D recipients tested still had greater than or equal to 0.15 microgram/ml and more than half had greater than or equal to 1.0 microgram/ml antibody protein.     

Immunologic priming to capsular polysaccharide in infants immunized with Haemophilus influenzae type b polysaccharide-Neisseria meningitidis outer membrane protein conjugate vaccine

Thirty children vaccinated at 2 to 17 months of age with Haemophilus influenzae type b polysaccharide linked to a partially purified 40,000 dalton outer membrane protein of Neisseria meningitidis were revaccinated 10 to 14 months later with conventional H. influenzae type b polysaccharide vaccine. The geometric mean anti-type b antibody concentration before reimmunization was 0.68 micrograms/mL, and rose to 31 micrograms/mL in sera obtained 1 month later. The mean level after immunization was not significantly different than that in sera from 12 adults immunized with type b polysaccharide vaccine (51 micrograms/mL, P = 0.3), and was 10-fold higher than that of 13 control children immunized with type b polysaccharide for the first time (2.7 micrograms/mL, P less than 0.001). The IgG responses of the children first given conjugate vaccine and then conventional type b polysaccharide vaccine were of a similar magnitude as those in the immunized adults. Further, the children maintained high levels of serum antibody 6 to 8 months later. Ten other children vaccinated in infancy with conjugate vaccine, and again with conjugate vaccine 10 to 15 months later, showed similar antibody responses to those of the group given conjugate vaccine in infancy, and booster with conventional polysaccharide vaccine. Thus vaccination with H. influenzae type b polysaccharide-outer membrane protein conjugate vaccine primes the immune system to an IgG memory antibody response to either type b polysaccharide or conjugate vaccine. Post-booster sera from all children tested showed high titers of functional activity in a complement-mediated bactericidal assay. These data suggest that protection of most infants from type b Haemophilus disease may be achieved by a combination of immunization at 2 to 4 months of age with this conjugate vaccine, and reimmunization 1 year later with conjugate or conventional type b polysaccharide vaccine.     

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.     

Safety evaluation of PRP-D Haemophilus influenzae type b conjugate vaccine in children immunized at 18 months of age and older: follow-up study of 30,000 children

We evaluated the safety of the PRP-D conjugate Hib vaccine (ProHIBit, Connaught) in 29,309 children vaccinated at 18-60 months of age in the Southern California Kaiser Permanente medical clinics during the period April 1, 1988, to July 31, 1989. Surveillance for potential reactions involved postcard questionnaires, telephone surveys, reports of Kaiser staff and review of hospitalizations and covered two periods following immunization: (1) the first 48 hours and (2) days 2 through 30. Surveillance for invasive Hib disease involved the above methods in addition to systematic reviews of laboratory and hospital records through January 31, 1990. Rates of local and systemic reactions within 48 hours of vaccination with PRP-D alone were low (less than or equal to 2% for fever greater than 102 degrees F, local redness or swelling) and similar to those previously reported after vaccination with PRP. Hospitalization and seizures (0.15% and 0.09% of vaccinated children, respectively) occurring within 1 month of immunization appeared to be unrelated to vaccination. One 29-month-old child had onset of a fatal episode of Hib sepsis/meningitis within 48 hours of vaccination. Also, a 30-month-old child developed Hib meningitis 10 months after PRP-D vaccination. We conclude that PRP-D is safe when given alone or in combination with other childhood vaccines between 18 and 60 months of age.     

Epidemiology of invasive Haemophilus influenzae type b disease among children in Finland before vaccination with Haemophilus influenzae type b conjugate vaccine

On the basis of intensified surveillance in Finland we report the epidemiology of invasive Haemophilus influenzae type b disease based on 333 consecutive culture-proved cases recorded during 1985 and 1986. The annual incidence rate among children younger than 5 years of age was 52/100,000; 46% of patients had meningitis, 29% had epiglottitis and 25% had other forms of invasive disease. The median age of patients was 27 months, with 45% younger than 2 years of age. Meningitis and epiglottitis were found more often among boys than among girls, whereas the opposite was found among patients with other types of invasive disease (P = 0.015). Among the latter 68% of children with pneumonia or septicemia were 2 years or older compared with 32% of patients with arthritis, cellulitis or pyelonephritis (P = 0.009). These background data are essential for correct interpretation and application of results from trials with H. influenzae type b conjugate vaccines that are currently ongoing in Finland.     

Value of antigen quantitation in Haemophilus influenzae type b meningitis

We studied Haemophilus influenzae type b meningitis in 68 patients to evaluate whether quantitative determination of PRP in body fluids obtained at admission or measurement of the duration of its presence helped identify patients at risk for complications. Geometric mean admission PRP concentrations in CSF, blood, and urine increased with severity of disease, but individual values varied greatly. Measurements of the duration of antigenemia and antigenuria also varied widely and were best predicted by the admission or peak PRP concentration. The mean duration of both antigenemia and antigenuria increased with severity of disease. In contrast, the elimination half-life of PRP did not differ significantly with severity of hospital course, peak PRP concentration in blood or urine, or patient age. Clearance from CSF could not be accurately assessed, but PRP was detectable in only six of 41 patients in whom spinal fluid was obtained after the eighth day of hospitalization; all had complicated courses. Although latex particle agglutination assay is a valuable aid in rapid diagnosis of invasive Hib infections, the predictive value of antigen quantitation at admission and the determination of its duration in body fluids is limited by the wide range of observed values.     

Immune memory in children previously vaccinated with an experimental quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine

BACKGROUND: In a previous study, a meningococcal diphtheria toxoid conjugate vaccine (MCV-4) triggered robust bactericidal antibody responses against serogroups A, C, Y, and W-135 in 2- to 10-year-old children. A subset of participants, 2 to 3 years of age at the initial vaccination, was evaluated for persistence of antibody, immune memory, and antibody avidity. METHODS: Participants were healthy children vaccinated 23 to 36 months earlier with MCV-4 (primed) or newly recruited meningococcal vaccine-naive 4-year-olds. Participants in both groups were alternately allocated to provide sera 8 or 28 days after administration of one tenth of the recommended dose of a meningococcal polysaccharide vaccine (PSV-4). Immune responses were assessed in sera obtained at baseline and either 8 or 28 days after reduced-dose PSV-4 administration. Safety was monitored. RESULTS: Before PSV-4 challenge, serum bactericidal antibody geometric mean titers (SBA GMTs) were higher for all 4 serogroups in the MCV-4-primed group than in the vaccine-naive group. SBA GMTs, geometric mean concentrations of immunoglobulin G (IgG) and geometric mean avidity indices for all 4 serogroups were significantly higher among MCV-4-primed versus vaccine-naive participants in the cohorts evaluated at 8 or 28 days after PSV-4 challenge. Adverse events were generally mild, self-limited, and comparable in all groups of children. CONCLUSIONS: Persistence of bactericidal antibody was seen for 23 to 36 months after a primary dose of MCV-4 in young children. Booster responses and avidity maturation were evident after a challenge with reduced-dose polysaccharide vaccine.     

Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland.

A recently developed Haemophilus influenzae type b capsular polysaccharide vaccine was given to 48,977 children 3 months to 5 years of age; an equal number of children receiving group A meningococcal vaccine served as controls. The protection as well as serum antibody response was strongly age-dependent. Among children who had received the H. influenzae type b vaccine when 18 months of age or older, there were no cases of bacteremic disease caused by H. influenzae type b in the first year after vaccination. At the same time 11 such cases were seen in the control group of the same age, a highly significant difference. In the second year after vaccination two cases occurred in the H. influenzae type b-vaccinated group, five in the meningococcal-group A vaccinated group. No protection was seen among children who had been younger than 18 months when vaccinated, even if they received a booster dose of the vaccine. The serum antibody response to the H. influenzae type b polysaccharide, measured by radioimmunoassay, was poor in children below 18 months of age and good in those above it. No effect of the vaccine could be seen on the nasopharyngeal carriage of H. influenzae type b, which was approximately 6% in this age group. Adverse effects of the vaccine were mild.     

Safety and antibody persistence following Haemophilus influenzae type b conjugate or pneumococcal polysaccharide vaccines given before pregnancy in women of childbearing age and their infants

BACKGROUND: Immunization of healthy women before pregnancy is a potential approach to providing increased levels of maternal antibody to newborns to protect them from infections occurring during the perinatal period and first months of life. METHODS: Healthy nonpregnant Pima Indian women of childbearing age were randomized to receive one of two Haemophilus influenzae type b (Hib) conjugate vaccines [HbOC or Hib-meningococcal outer membrane protein complex (OMP)] or a 23-valent pneumococcal polysaccharide vaccine (PnPs). Infants received Hib-OMP vaccine at 2, 4 and 12 months of age. Vaccine safety and immunogenicity was evaluated in the women and their infants. RESULTS: Anti-polyribose ribitol phosphate antibody titers were significantly higher in women in both Hib conjugate vaccine groups than in the pneumococcal vaccine group throughout the 37-month observation period. Antibody responses to HbOC vaccine were significantly higher than those to Hib-OMP. A subsequent booster dose of each Hib conjugate vaccine induced reactions and antibody responses similar to those of the first dose. Infants born to mothers immunized with Hib vaccines compared with PnPs had significantly higher polyribose ribitol phosphate-specific IgG antibody titers at birth and 2 months of age but lower antibody responses to Hib-OMP at 6 months and similar titers before and after boosting with Hib-OMP at 1 year of age. By contrast women immunized with PnPs did not have significantly elevated concentrations of pneumococcal-specific antibody at delivery, and their infants had pneumococcal antibody titers similar to those of infants born to mothers who did not receive pneumococcal vaccine before pregnancy. CONCLUSION: Hib conjugate vaccine given to women before pregnancy significantly increased the proportion of infants who had protective Hib antibody levels at birth and 2 months of age.