Immune response to Haemophilus influenzae type b conjugate vaccine in preterm infants

Background: Haemophilus influenzae type b (Hib) vaccine became available for use in Japan in December 2008. The aim of the present study was to evaluate the immunogenicity of Hib vaccine in Japanese preterm infants. Methods: Serum samples were obtained from 54 preterm infants before the first vaccination and 1 month after the third. Anti‐polyribosylribitol phosphate (PRP) antibodies were measured using an enzyme‐linked immunosorbent assay method. Antibody positivity was defined as levels >1 µg/mL. Results: Of the 54 preterm infants, 46 (85.2%) achieved antibody levels >1 µg/mL. This compares with the 92.4% reported in full‐term infants. The antibody seroconversion rate of infants starting vaccination at 2 months of age was close to being significantly lower than when vaccination was started at 3 months of age (P= 0.060). In addition, the percentage of infants achieving a positive response in the group with a history of antenatal steroid exposure was significantly higher than in those not exposed (P= 0.046). Thus, risk factors for lower Hib antibody concentrations after three doses of vaccine were age at first vaccination and lack of use of antenatal steroids. Conclusions: There is a possibility that perinatal factors and the environment unique to preterm infants are related to their lower antibody positivity rates compared to full‐term infants. It may therefore be preferable to modify the proposed immunization schedule.     

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.     

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.     

Depression of anticapsular antibody after immunization with Haemophilus influenzae type b polysaccharide-diphtheria conjugate vaccine

Invasive Haemophilus influenzae type b infections have been observed in the week after immunization with capsular polysaccharide vaccine. We sought to document depression of antibody concentrations after immunization of 18-month-old infants with H. influenzae type b capsular polysaccharide-diphtheria conjugate vaccine. All 9 infants with detectable preimmunization anticapsular antibody had depression of antibody concentrations on the second day after immunization (P = 0.002). By Day 7 all had achieved anticapsular antibody concentrations greater than 0.15 micrograms/ml, a level believed to provide protection to immediate challenge with H. influenzae type b. Of those without detectable preimmunization antibody, 7 of 21 (33%; 95% confidence interval, 11 to 56%) had not achieved concentrations of greater than 0.15 mg/ml 1 week after immunization. We conclude that there is depression of anticapsular antibody concentrations during the first week after immunization with H. influenzae type b capsular polysaccharide-diphtheria conjugate vaccine. We speculate that H. influenzae type b infections after immunization with H. influenzae type b vaccines may be the result of: (1) low antibody concentrations because of either depression of antibody concentrations or failure to develop antibody; and (2) exposure to H. influenzae type b. Depression of antibody concentrations could be explained by binding of in vivo antibody to the vaccine.     

Immunization after invasive Haemophilus influenzae type b disease. Serologic response to a conjugate vaccine

Fifteen children with previous invasive Haemophilus influenzae type b disease were immunized with a Hemophilus-diphtheria toxin mutant protein conjugate vaccine. Serologic responses were compared with those of 31 newly immunized children without previous invasive H influenzae type b disease. Mean levels of antibody to polyribosylribitol phosphate among study children younger than 18 months were 0.086 mg/L before immunization, 0.737 mg/L after first immunization, and 4.453 mg/L after second immunization. In contrast, the comparable mean polyribosylribitol phosphate antibody levels among control children younger than 18 months were 0.107, 3.580, and 63.502 mg/L. A similar pattern of results was found among children aged 18 months or older. Although children with previous invasive H influenzae type b disease do not respond as vigorously to conjugate vaccine as do previously healthy controls, the response is sufficient to justify routine immunization of such children.     

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure

Aims: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. Methods: Unmatched case-control study in the UK and Eire 1992–2001 and Victoria, Australia 1988–1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. Results: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 µg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 µg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 µg/ml (2.78 to 5.15); unvaccinated GMC 1.48 µg/ml (0.90 to 2.21); p = 0.003). Conclusions: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.     

IgG subclass response to immunization with Haemophilus influenzae type b polysaccharide-outer membrane protein conjugate vaccine

We immunized 117 children with either Haemophilus influenzae type b polysaccharide vaccine or type b polysaccharide coupled to an outer membrane protein of group B Neisseria meningitidis (conjugate vaccine), and measured the IgG, IgG1, and IgG2 subclass composition of antibody to type b polysaccharide in postimmunization sera by ELISA. The IgG responses of 51 children, 24-83 months of age, immunized for the first time with the conventional type b vaccine consisted of both IgG1 and IgG2 antibody (respective geometric means of 2.24 and 0.77 micrograms/ml). In contrast, the IgG responses of 28 infants, 2-17 months of age, immunized with conjugate vaccine were predominantly or exclusively IgG1 (genometric mean IgG1 and IgG2 antibody concentrations of 1.92 and 0.19 micrograms/ml). A total of 38 children was primed with conjugate vaccine between 2 and 17 months of age and boosted approximately 1 yr later. The 28 children boosted with type b polysaccharide vaccine showed memory antibody responses consisting of both IgG1 and IgG2 (respective geometric means of 12.7 and 4.8 micrograms/ml); the 10 children boosted with conjugate vaccine showed a similar pattern of IgG subclass responses (respective geometric means of 20.8 and 5.1 micrograms/ml, p greater than 0.4 compared to the respective geometric mean IgG1 and IgG2 values of the group boosted with polysaccharide). Thus, in children 24-83 months of age, immunization with conventional type b polysaccharide vaccine generally elicits both IgG1 and IgG2 responses, with a slight predominance of IgG1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunogenicity of Haemophilus b conjugate vaccine (meningococcal protein conjugate) in children with prior invasive Haemophilus influenzae type b disease

Children younger than 2 years of age with previous invasive Haemophilus influenzae (Hib) type b disease may not develop protective antibodies to antigens of Hib and may be at risk of developing a second episode of Hib disease. Twenty-three children with prior Hib disease were immunized with Haemophilus b conjugate vaccine (meningococcal protein conjugate). Children 12 to 24 months of age were given one dose of vaccine and children younger than 12 months of age were given 2 doses 2 months apart. Antibody to the polysaccharide capsule of Hib (PRP) was measured by radioimmunoassay. Eighteen children had preimmunization serum antibody concentrations less than 0.150 micrograms/ml. All 18 children responded with greater than 0.150 micrograms/ml of antibody after a single dose of vaccine. Only 1 of the 23 children had a preimmunization serum antibody concentration greater than 1.000 micrograms/ml. Seventeen children ultimately responded with greater than 1.000 micrograms/ml of antibody (P less than 0.0001), concentrations of antibody thought to correlate with protection. Haemophilus b conjugate vaccine (meningococcal protein conjugate) is immunogenic in children with invasive Hib disease. Children younger than 2 years of age with invasive Hib disease should be subsequently immunized with a Hib conjugate vaccine.     

Serologic responses to an Haemophilus influenzae type b polysaccharide-Neisseria meningitidis outer membrane protein conjugate vaccine in very young Gambian infants

Recent studies in the United States and Europe have shown that Haemophilus influenzae type b polysaccharide-protein conjugate vaccines can induce protective antibody levels in young infants, but it was not clear that this would be the case in African infants, to whom H influenzae vaccines must be given at a very early age to prevent disease caused by H influenzae. Therefore, antibody responses to an H influenzae type b polysaccharide-Neisseria meningitidis outer membrane protein conjugate vaccine were measured in very young Gambian infants. In the first group (n = 85), to whom the vaccine was given at the ages of 1 and 3 months, the geometric mean antibody level rose from a prevaccination level of 0.23 microgram/mL to a postvaccination level of 1.27 micrograms/mL, and in the second group (n = 56), vaccinated at the ages of 2 and 4 months, the prevaccination level of 0.16 microgram/mL rose to a postvaccination level of 1.59 micrograms/mL. These two final postvaccination levels did not differ significantly, and interpolation suggests that similar antibody levels were present in both groups of infants at the age of 3 months. This is the age by which protection would need to be achieved to protect against H influenzae meningitis in The Gambia and in other countries where the infection has similar epidemiologic characteristics. No significant side effects of vaccination were noted.     

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure.

AIMS: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. METHODS: Unmatched case-control study in the UK and Eire 1992-2001 and Victoria, Australia 1988-1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. RESULTS: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 microg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 microg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 microg/ml (2.78 to 5.15); unvaccinated GMC 1.48 microg/ml (0.90 to 2.21); p = 0.003). CONCLUSIONS: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.     

Immunogenicity of Haemophilus influenzae type b conjugate vaccine in children with sickle cell disease.

OBJECTIVE--To determine the safety and immunogenicity of Haemophilus influenzae type b conjugate vaccine in children with sickle cell disease. RESEARCH DESIGN--Prospective, nonrandomized, nonblinded study. SETTING--Hospital-based, comprehensive sickle cell center. PATIENTS--Children with sickle cell disease aged 18 months to 18 years who were previously unvaccinated or had an inadequate or waning response to H influenzae type b polysaccharide vaccine. SELECTION PROCEDURES--Consecutive eligible patients. INTERVENTIONS--Vaccination and observation for adverse effects. Blood samples were taken before and 1 to 2 and 6 months after vaccination to measure anticapsular antibody levels. MEASUREMENTS AND RESULTS--Vaccination was well tolerated. One hundred percent and 96% of the 31 immunized children had postvaccination anticapsular antibody concentrations of greater than 0.15 and 1.0 mg/L, respectively. Six months after vaccination, 100% and 89% of children had these antibody concentrations. CONCLUSIONS--H influenzae type b conjugate vaccines are safe and highly immunogenic in children with sickle cell disease. It is likely that these vaccines will be protective against invasive H influenzae type b disease.     

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.     

Clinical trials of the Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine

To date in the United States over 3000 subjects under 2 years of age have received 1 or more doses of PRP-D vaccine. Thus far there have been no statistically significant differences between the rate of local or systemic reactions among recipients of this vaccine and that among those who received the PRP or placebo control vaccines. The vaccine is well-tolerated and is not associated with clinically significant adverse reactions. The PRP-D vaccine has been shown to be a T cell-dependent immunogen, inducing sequential increases in antibody level with repeated immunization and producing a high proportion of IgG relative to IgM. A recall response, or immunologic memory effect, has been demonstrated in children 1 year after receiving PRP-D. PRP-D is consistently immunogenic in all age groups. In adults this vaccine induces a geometric mean antibody response greater than 200 micrograms/ml. In infants 7 to 24 months of age levels greater than 1 microgram/ml have been achieved in over 90% of the subjects with 1 or 2 doses of PRP-D, whereas 90% or more of infants under 7 months of age achieve levels of 0.15 microgram/ml or greater.