Clinical and immunologic responses to the capsular polysaccharide of Haemophilus influenzae type b alone or conjugated to tetanus toxoid in 18- to 23-month-old children

The safety and immunogenicity of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) alone, or covalently bound to tetanus toxoid in saline solution (Hib-TT) or adsorbed onto AI(OH)3 (Hib-TT ads), were evaluated after one injection into 18- to 23-month-old healthy children in Sweden. No side reactions were elicited by Hib CPS; side reactions elicited by the two conjugates were similar and comparable to those reported for diphtheria and tetanus toxoids adsorbed. Hib-TT was the most immunogenic of the three vaccines, eliciting about 10-fold higher antibody levels than Hib CPS; of 28 vaccinees, all had greater than 1.0 microgram Ab/mL serum after immunization with Hib-TT. Increases of Hib CPS antibodies within immunoglobulin classes induced by the three vaccines were, in decreasing order, IgG greater than IgM greater than IgA. Within IgG subclasses, rises in IgG1 Hib CPS antibodies were the most frequent, followed by IgG2; some vaccinees with high postimmunization levels also had rises in IgG3 and one in IgG4. Immunization-induced Hib CPS antibodies were bactericidal. Hib-TT also elicited higher levels of tetanus toxoid antibodies than Hib-TT ads; these tetanus toxoid antibodies neutralized tetanus toxin in vivo.     

Antibodies against Haemophilus influenzae type b capsular polysaccharide and tetanus toxoid before and after a booster dose of the carrier protein nine years after primary vaccination with a protein conjugate vaccine

IgG antibodies against Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) and tetanus toxoid (TT) were measured for 53 children, 10 years of age, before and 1 month after a booster dose of diphtheria-tetanus vaccine (DT). All children had been vaccinated at 3, 5 and 12 months of age with DT and a Hib-TT conjugate. Geometric mean concentrations of Hib CPS serum IgG antibody were 4.16 and 4.30 microg/mL before and after the DT booster, respectively. The geometric mean concentration of TT IgG antibody increased from 0.09 IU/mL to 4.58 IU/mL (P < 0.001). Hib CPS IgG levels remained well above protective titers for 9 years after 3 doses of Hib-TT appropriately spaced in infancy. A booster dose of TT did not affect Hib CPS antibody concentrations but induced a pronounced IgG response against TT.     

Evaluation of the vaccination of 3-month-old infants with Haemophilus influenzae type B (Hi b) capsular polysaccharide conjugated to tetanus protein (PRT-T) Pediatric Group of the Lyon Region]

Haemophilus influenzae type b (Hi b) is responsible for severe invasive infections, particularly meningitis, in children under 5 years of age, with the greatest frequency between 6 and 18 months. The antigenicity of Hib is related to its capsular polysaccharide (polyribosyl-ribitol-phosphate or PRP) which is at the origin of the production of bactericide anti-PRP antibodies. Vaccine using PRP alone have been shown to be well tolerated and immunogenic, but only in children above 2 years of age. We vaccinated 365 infants starting at the age of 3 months with a vaccine using a PRP-tetanus toxoid conjugate (PRP-T), coupled with the DTP pertussis vaccine. Local and general tolerance was found to be very good. Quantitative serum antibody measurements showed excellent immunogenicity. None of the vaccinated infants presented an invasive Hib infection. It therefore appears that early systematic vaccination of infants with PRP-T vaccine should be encouraged.     

Combined diphtheria, tetanus, pertussis, and Haemophilus influenzae type b vaccines for primary immunisation

A total of 146 infants were immunised at ages 2, 3, and 4 months with a combined diphtheria, tetanus, pertussis (DTP)--Haemophilus influenzae type b (Hib) tetanus toxoid conjugate (PRP-T) vaccine (Pasteur Merieux) to assess the antibody response and adverse events associated with immunisation. Adverse events, including fever, were recorded by parents in a diary for three days following each injection. Blood was taken before the first immunisation and four weeks after the third immunisation to assess antibody response. Data were compared with those from historical controls who had received DTP and PRP-T vaccines by separate injection. The combined vaccine was well tolerated. Rates of local and general reactions were similar to those reported for infants immunised by separate injection. All infants achieved protective antibody titres (> 0.01 IU/ml) for diphtheria and tetanus; 98% acquired Hib (PRP) antibody > 0.15 microgram/ml and 82.5% > 1.0 microgram/ml. Pertussis antibody titres (pertussis toxin, filamentous haemagglutinin, total agglutinins, and agglutinins 2 and 3) showed appreciable rise following immunisation. DTP and PRP-T vaccines provide similar antibody responses and adverse effects whether mixed in the same syringe or administered by separate injection. The vaccines could be combined for use in the United Kingdom primary immunisation schedule.     

Persistence of serum antibodies elicited by Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infants vaccinated at 3, 5 and 12 months of age

Eighty-five children received three injections of a vaccine consisting of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) conjugated to tetanus toxoid (TT) (Hib-TT) at 3, 5 and 12 months of age according to the vaccination schedule for Swedish children. Diphtheria-tetanus toxoid vaccine was concurrently injected at another site. Two dosages, 7.5 and 15 micrograms, of Hib CPS were studied. No serious reactions occurred. Hib-TT elicited fewer local reactions than diphtheria-tetanus toxoid vaccine. Significant increases in Hib CPS serum antibodies occurred after all injections in both dosage groups with virtually no differences between the two groups. After the first and second injections geometric mean serum antibody concentrations of both dosage groups combined increased to 0.49 and 3.71 micrograms/ml and 81 and 99% of the vaccinees, respectively, had concentrations greater than 0.15 micrograms/ml. After the third dose geometric mean concentrations increased to 13.7 micrograms/ml and all had concentrations greater than 0.15 micrograms/ml. The geometric mean Hib CPS antibody concentrations decreased to 1.24 micrograms/ml 18 months after the third injection, but 97% still had concentrations greater than 0.15 micrograms/ml. The rise of Hib CPS antibodies was mostly in the IgG class. The most pronounced increase was seen in the IgG1 subclass but there were also increase in IgG2 and IgG3. Protective concentrations of TT antibodies were found in all postimmunization sera. In conclusion Hib-TT is safe and immunogenic in infants and should be protective from 6 to 30 months and probably longer thereafter.     

Combined diphtheria,tetanus, pertussis,and Haemophilus influenzae type b vaccines for primary immunisation.

A total of 146 infants were immunised at ages 2, 3, and 4 months with a combined diphtheria, tetanus, pertussis (DTP)--Haemophilus influenzae type b (Hib) tetanus toxoid conjugate (PRP-T) vaccine (Pasteur Merieux) to assess the antibody response and adverse events associated with immunisation. Adverse events, including fever, were recorded by parents in a diary for three days following each injection. Blood was taken before the first immunisation and four weeks after the third immunisation to assess antibody response. Data were compared with those from historical controls who had received DTP and PRP-T vaccines by separate injection. The combined vaccine was well tolerated. Rates of local and general reactions were similar to those reported for infants immunised by separate injection. All infants achieved protective antibody titres (> 0.01 IU/ml) for diphtheria and tetanus; 98% acquired Hib (PRP) antibody > 0.15 microgram/ml and 82.5% > 1.0 microgram/ml. Pertussis antibody titres (pertussis toxin, filamentous haemagglutinin, total agglutinins, and agglutinins 2 and 3) showed appreciable rise following immunisation. DTP and PRP-T vaccines provide similar antibody responses and adverse effects whether mixed in the same syringe or administered by separate injection. The vaccines could be combined for use in the United Kingdom primary immunisation schedule.     

Haemophilus influenzae type b conjugate vaccine diluted tenfold in diphtheria-tetanus-whole cell pertussis vaccine: a randomized trial

BACKGROUND: Despite their proven efficacy Haemophilus influenzae type b (Hib) conjugate vaccines are not given to most children in the developing world in the face of an estimated global Hib disease burden of nearly 2 million cases per annum. A major barrier to the introduction of the vaccine would be overcome by diluting the vaccine 10-fold in diphtheria-tetanus-whole cell pertussis (DTP). We report a randomized trial comparing the use of Hib conjugate vaccine diluted in a multidose vial of DTP with that of the full Hib dose. METHODS: We randomized 168 infants to receive either the full dose Hib polysaccharide-tetanus toxoid conjugate (PRP-T) vaccine or a 1/10 dilution prepared by reconstituting the full dose in a 10-dose DTP vial. Infants were vaccinated at 6, 10 and 14 weeks of age and received a full dose as a test of immunologic memory at 9 months of age. Sera were collected at each visit and at 1 week after the booster dose. Serum anti-capsular PRP antibody concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: After the primary vaccination series, 95% of infants in the full dose arm and 94% of infants in the 1/10 dose arm achieved anti-PRP IgG antibody concentrations of > or = 1.0 microg/ml. Infants receiving the diluted vaccine had significantly higher titers of anti-PRP antibody in response to the booster dose (151.36 microg/ml vs. 68.55 microg/ml, P = 0.009). CONCLUSIONS: The 1/10 dose of PRP-T was as immunogenic and safe as the full dose. The technique of diluting a single dose of PRP-T in a 10-dose DTP vial could potentially allow the widespread introduction of Hib vaccine in resource-poor countries currently unable to afford full dose Hib conjugate vaccine.     

Studies on Pneumococcus vaccine alone or mixed with DTP and on Pneumococcus type 6B and Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugates in two- to five-year-old children with sickle cell anemia

Pneumococcus vaccine, injected alone or mixed with diphtheria-tetanus toxoid-pertussis, did not elicit significant concentrations of pneumococcus type 6 antibodies in 2- to 5-year-old sickle cell anemia patients (n = 22). Reinjection 5 months later failed to elicit a booster response to pneumococcus type 6. We then injected conjugates of pneumococcus type 6B and of Haemophilus influenzae type b (Hib), each bound to tetanus toxoid (TT), alternatively at monthly intervals into sickle cell anemia patients of the same age group (n = 25); most received 3 injections of each vaccine. Pneumococcus vaccine was administered to 19 patients and Hib to 1 at approximately 1 year of age. Blood samples were taken before each and approximately 6 months after the last injection. Infrequent and minimal local reactions and only 6 episodes of fever (3%) occurred after injection of the conjugates. Pneumococcus type 6B-TT elicited a rise in the geometric mean concentration of pneumococcus type 6 antibodies (Ab) from 104 ng of antibody nitrogen (AbN)/ml in preimmunization sera to 385 ng of AbN/ml after the first injection (P less than 0.01). There were further increases after the 2 subsequent injections; 6 months after the third injection, the mean concentration was 940 ng of AbN/ml and 15 of 16 (94%) had greater than 300 ng of AbN/ml. Hib-TT elicited a 160-fold increase of Hib antibodies to a geometric mean concentration of 39.0 micrograms of Ab/ml after the first injection. These levels rose approximately 2-fold following 2 additional injections to 71.7 micrograms/ml and declined to 10.7 micrograms/ml at the 6-month sampling.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical and immunologic responses to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infants injected at 3, 5, 7, and 18 months of age

The safety and immunogenicity of Haemophilus influenzae type b-tetanus toxoid conjugate vaccine (Hib-TT) were evaluated in 77 healthy infants receiving injections at 3, 5, 7, and 18 months of age. No serious local or systemic reactions were noted. After the first injection the geometric mean Hib antibody level rose to 0.55 micrograms/ml, and each subsequent injection elicited a statistically significant rise in the geometric mean. The percentage of vaccinees with Hib antibody levels greater than 0.15 micrograms/ml serum was 75.5% after the first, 97.4% after the second, and 100% after the third Hib-TT injection. This percentage fell to 90.9% at 18 months of age but rose again to 100% after the fourth injection. Control infants (n = 10) injected with diphtheria-tetanus toxoid-pertussis vaccine only had nondetectable levels after the second injection. Hib-TT elicited increases of Hib antibody in all isotypes: IgG greater than IgM greater than IgA. Among IgG subclasses the highest increases were of IgG1. All vaccinated subjects had greater than 0.01 U/ml of TT antibody (estimated protective level) throughout the study. We conclude that Hib-TT, injected at 3, 5, 7, and 18 months, is safe and induces protective levels of antibodies during the age of highest incidence of meningitis caused by Hib.     

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.     

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.     

The safety and immunogenicity of an heptavalent pneumococcal polysaccharide conjugate vaccine (Prevenar) administered in association with a whole-cell pertussis-based pediatric combination vaccine (DTP-IPV/PRP-T) to French infants with a two-, three-, and four-month schedule]

Invasive pneumococcal disease is presently a leading cause of mortality due to bacterial infectious diseases in French children less than 2 years of age, and only the pneumococcal conjugate vaccines induce a protective immune response for those within this vulnerable age group. MATERIAL AND METHODS: The safety and immunogenicity of a heptavalent pneumococcal polysaccharide conjugate vaccine (PREVENAR was tested in French infants immunized with the 2, 3 and 4 month French schedule as part of an open, randomized, comparative clinical study, in association with a whole-cell pertussis-based pediatric combination vaccine. RESULTS: In the PREVENAR plus DTP-IPV/Hib association group, 90.6-100% of children achieved a post-dose three threshold IgG concentration of >0.15 microg/ml against each of the seven pneumococcal serotypes. Regarding immunogenicity, no interference with the antibody response to the various antigenic components of the DTP-IPV/Hib vaccine was observed. Local reactions were significantly less frequent at the PREVENAR injection site than at the DTP-IPV/Hib injection site; there was no increase in systemic adverse events in the vaccine association group compared to the DTP-IPV/Hib alone group, further exception of fever >38 degrees C which was more frequently reported in the PREVENAR + PENTACOQ group following the second dose of vaccines (56% vs. 35%); no serious adverse event could be considered to be related to the PREVENAR immunization in this study. CONCLUSION: The heptavalent pneumococcal conjugate vaccine is immunogenic when administered at 2, 3 and 4 months. PREVENAR can be administered simultaneously with the DTP-IPV/Hib combination vaccine.     

Immunogenicity of Haemophilus influenzae type b conjugate vaccines in infant rhesus monkeys

Two Haemophilus influenzae type b (Hib) polysaccharide-protein conjugate vaccines were evaluated for immunogenicity in eliciting anti-polyribosyl ribitol phosphate (PRP) antibodies in infant rhesus monkeys. Animals received intramuscular injections of either Hib polysaccharide (PRP)-meningococcal outer membrane protein complex or Hib oligosaccharide-CRM197 (HbOC) conjugate vaccines on d 0, 28, and 56. Because HbOC contains the CRM197 mutant diphtheria toxin from Corynebacterium diphtheriae as its protein carrier, the effect of simultaneous injection of diphtheria toxoid on the immunogenicity of HbOC also was evaluated by dividing monkeys vaccinated with HbOC into three groups: HbOC/saline, HbOC/diphtheria and tetanus toxoids, and HbOC/tetanus toxoid (coadministration of HbOC and other vaccine or placebo injected into the flank muscle of different legs). Infant monkeys vaccinated with the PRP-outer membrane protein complex conjugate responded with anti-PRP antibody after the first dose and showed booster responses after the second and third injections. In contrast, infant monkeys vaccinated with HbOC did not respond after three doses of HbOC/saline or HbOC/tetanus toxoid. However, two of three monkeys given concurrent injections of HbOC and diphtheria and tetanus toxoids did respond. The nonresponder monkey to three doses of HbOC and diphtheria and tetanus toxoids did respond to a subsequent injection with PRP-outer membrane protein complex. Thus, concomitant administration of diphtheria toxoid, a common vaccine for human infants, is necessary to elicit an anti-PRP antibody response to HbOC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunogenicity of Haemophilus influenzae type b polysaccharide-outer membrane protein conjugate vaccine in patients who acquired Haemophilus disease despite previous vaccination with type b polysaccharide vaccine

To investigate the basis of the immune defect in children who acquire invasive Haemophilus disease despite previous vaccination with Haemophilus influenzae type b (Hib) polysaccharide vaccine, we determined the ability of vaccine failure patients with low levels of serum anticapsular antibody (less than 1 microgram/ml) to respond to reimmunization. Thirty-four patients, ranging in age from 27 to 61 months, were vaccinated with either Hib polysaccharide (n = 20) or Hib polysaccharide-outer membrane protein conjugate vaccine (n = 14). All but three of the children had normal serum concentrations of immunoglobulins, including IgG2. The geometric mean serum anticapsular antibody concentration of the group given polysaccharide vaccine increased from 0.27 microgram/ml before vaccination to 0.65 microgram/ml 1 month later (p less than 0.05), but the magnitude of the response was nearly 10-fold less than that of 31 age-matched control children given polysaccharide vaccine (6.3 micrograms/ml, p less than 0.001). In contrast, all 14 patients with vaccine failure who were given conjugate vaccine showed increases of fivefold or more in serum anticapsular antibody (geometric means 0.35 and 12.8 micrograms/ml, respectively; p less than 0.001). All patients with vaccine failure who did not respond to polysaccharide vaccine were subsequently given conjugate vaccine, and all had high antibody responses. Most patients tested showed increases in complement-mediated serum bactericidal activity. These data suggest that immunization with conjugate vaccine confers protection against Hib disease to children who, because of genetic or other reasons, cannot respond to the unconjugated form of the polysaccharide vaccine.     

Differences in the immunogenicity of three Haemophilus influenzae type b conjugate vaccines in infants.

OBJECTIVE: To compare the immunogenicity of three Haemophilus influenzae type b (Hib) conjugate vaccines in infants residing in different geographic areas. DESIGN: A multicenter, randomized immunogenicity trial with sera assayed in one laboratory without knowledge of vaccine brand status. In Minneapolis and Dallas, infants were vaccinated at 2, 4, and 6 months of age; in St. Louis, infants were vaccinated at 2 and 4 months of age. SUBJECTS: A convenience sample of 458 infants recruited largely from private pediatric practices. MEASUREMENTS AND RESULTS: At each of the study sites, the respective trends between the anticapsular antibody responses of the infants assigned to the different conjugate vaccine groups were similar. After one or two doses, Hib polysaccharide conjugated to outer membrane protein complex of Neisseria meningitidis (PRP-OMP) was more immunogenic than Hib polysaccharide-tetanus toxoid conjugate (PRP-T), or Hib oligomers conjugated to the mutant diphtheria toxin CRM197 (HbOC) (p less than 0.001). After two doses, PRP-T was more immunogenic than HbOC (p less than or equal to 0.001). After three doses there was no significant difference in the geometric mean antibody concentrations of the three groups, and 88% to 97% of the infants had greater than 1.0 microgram/ml of antibody. The HbOC vaccine elicited a 10-fold lower antibody response after two doses (0.45 micrograms/ml vs 5.9 micrograms/ml) and a threefold lower antibody response after three doses (6.3 micrograms/ml vs 22.9 micrograms/ml) than observed by us previously with a prelicensure lot of this vaccine (p less than 0.001). Because of these low responses, the infants in St. Louis who received two doses of HbOC were revaccinated with unconjugated PRP at a mean age of 8.9 months. This group was immunologically primed, as evidenced by a 10-fold increase in geometric mean antibody concentration after vaccination at an age when unprimed infants do not normally respond to this vaccine. CONCLUSIONS: In infants in three geographic regions, PRP-OMP elicited earlier acquisition of serum antibody than the other two conjugate vaccines; however, after three doses the antibody concentrations of the three groups were not significantly different. The reason for the markedly lower immunogenicity of HbOC vaccine than reported previously is unknown.     

Defining the burden of pneumonia in children preventable by vaccination against Haemophilus influenzae type b

OBJECTIVES: To determine the burden of pneumonia requiring hospitalization in infants and young children preventable by vaccination against Haemophilus influenzae type b (Hib). DESIGN: Vaccination centers in Santiago, Chile, were randomly selected to administer PRP-T, an Hib conjugate vaccine, combined with diphtheria-tetanus toxoids-pertussis (DTP) vaccine or DTP alone. SUBJECTS: Infants who received > or =2 doses of DTP or DTP and Hib conjugate vaccine combined. MAIN OUTCOME MEASURES: Pneumonia episodes leading to hospitalization accompanied by indicators of likely bacterial infection including radiologic evidence of alveolar consolidation or pleural effusion, an elevated erythrocyte sedimentation rate (> or =40 mm/h) or bronchial breath sounds on auscultation. RESULTS: In participants age 4 to 23 months, PRP-T reduced the incidence of pneumonia associated with alveolar consolidation or pleural effusion by 22% (95% confidence interval, -7 to 43) from 5.0 to 3.9 episodes per 1000 children per year. When the pneumonia case definition included any of the following, alveolar consolidation, pleural effusion, erythrocyte sedimentation rate > or =40 mm/h or bronchial breath sounds, PRP-T provided 26% protection (95% confidence interval, 7 to 44) and prevented 2.5 episodes per 1000 children per year. CONCLUSIONS: Hib vaccine provides substantial protection against nonbacteremic pneumonia, particularly those cases with alveolar consolidation, pleural effusion or other signs of likely bacterial infection. Hib vaccination prevented approximately 5 times as many nonbacteremic pneumonia cases in infants as meningitis cases, thus indicating that the largest part of the effect of Hib vaccination might be undetectable by routine culture methods.     

Vaccines to prevent neonatal GBS infection

Group B Streptococcus (GBS) remains the leading bacterial cause of neonatal sepsis and meningitis in the United States. Although antibiotic prophylaxis has decreased the infection rate, the best long-term solution lies in the development of effective vaccines. The GBS capsular polysaccharide (CPS) is a major target of antibody-mediated immunity. While antibody to CPS is protective, uncoupled CPS is variably immunogenic in humans, a finding that led to the development of GBS CPS-protein conjugate vaccines. GBS CPS-protein conjugate vaccines of all clinically important serotypes have been produced and tested in animals. Mice and baboons immunized with CPS conjugates transplacentally transferred functionally active GBS-specific IgG to their offspring. Phase 1 and phase 2 clinical trials have shown that GBS conjugate vaccines are safe, well-tolerated and immunogenic in healthy adults. Moreover, human antibodies elicited by the conjugate vaccines are functionally active both in vitro and in animal models of invasive GBS disease.     

Immunogenicity of a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine when mixed with a diphtheria-tetanus-acellular pertussis-hepatitis B combination vaccine

BACKGROUND: Combination vaccines are urgently needed to reduce the number of injections given to young children. The aim of the study was to evaluate the safety and immunogenicity of a combination vaccine that contains diphtheria and tetanus toxoids and acellular pertussis antigens (DTaP), recombinant hepatitis B surface antigen (HepB) and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus toxoid (PRP-T). METHODS: Four hundred five infants were randomized equally to three groups and immunized at 2, 4 and 6 months of age with: (1) DTaP/HepB vaccine used to reconstitute lyophilized PRP-T vaccine and administered as a single injection; (2) DTaP/HepB vaccine and PRP-T vaccine administered as two separate injections; or (3) DTaP, HepB and PRP-T vaccines administered as three separate injections. Safety was closely monitored, and blood specimens were obtained to assess antibody responses to each vaccine antigen. RESULTS: All study vaccines were well-tolerated, and the rates of systemic and injection site reactions were similar between groups. After the third dose the geometric mean antibody concentrations to Hib were significantly lower in subjects in Group 1 (1.63 microg/ml) compared with subjects in Groups 2 and 3 (6.26 and 6.15 microg/ml, respectively; P < 0.0001). Subjects with antibody concentrations <1.0 microg/ml after the third dose responded well to a booster dose of Hib conjugate vaccine given at 11 to 15 months of age (41 of 44 with anti-PRP > or = 1.0 microg/ml). Differences between groups for antibody responses to the other vaccine components were not clinically significant. CONCLUSIONS: Infants given a combined DTaP/ HepB/PRP-T vaccine experienced a significantly lower antibody response to the PRP-T component than infants given PRP-T vaccine as a separate injection. However, the immune response to a booster dose of Hib conjugate vaccine indicated the presence of immunologic memory.     

In vitro induction of IgG1 and IgG2 secretion by B cells of children who developed invasive haemophilus disease despite vaccination

Lymphocytes from seven patients who developed Haemophilus influenzae type b (Hib) disease after being vaccinated with Hib polysaccharide vaccine and from one patient who developed disease after conjugate vaccination were investigated for the ability to secrete IgG1 and IgG2, in vitro, in response to a combination of pokeweed and Staphylococcus aureus Cowan I mitogens. The eight patients were selected because they had low anticapsular antibody responses to Hib disease. Only one of the eight children had a history of previous severe, recurrent infections. This child (in whom a polysaccharide vaccine failed) had a deficiency of the second component of complement and also had a subnormal serum concentration of IgG4. Only one of the eight children, an otherwise healthy 54-mo-old with normal serum Ig concentrations, had subnormal mitogen-induced B-cell secretion of IgG1 and/or IgG2. When this child's lymphocytes were separated into T- and B-cell fractions and cocultivated with the respective fractions of the father's lymphocytes, the child appeared to have an intrinsic B-cell defect and normal T cells. There were no significant differences (p greater than 0.3) in the respective geometric means of the in vitro secretion of IgG1 or IgG2 of the B cells from the children with polysaccharide vaccine failure and those of 14 healthy controls of similar ages as the patients (IgG1, 1524 versus 3497 ng/mL per 10(5) lymphocytes; IgG2, 79 versus 89 ng/mL per 10(5) lymphocytes). Thus, despite the presence of impaired serum anticapsular antibody responses to Hib disease, most children who develop Hib disease after Hib polysaccharide vaccination have normal in vitro B-cell secretion of IgG1 and IgG2 in response to mitogens.     

Evidence for induction of polysaccharide specific B-cell-memory in the 1st year of life: plain Haemophilus influenzae type b - PRP (Hib) boosters children primed with a tetanus-conjugate Hib-DTPa-HBV combined vaccine

The lack of an adequate immune response to the major polysaccharide of the Haemophilus influenzae type b (Hib) capsule (polyribosyl ribitol phosphate) (PRP) in very young infants (<?18 months) can be overcome by conjugating PRP to a T-cell dependent carrier protein. We studied whether administration of a tetanus-PRP conjugate vaccine reconstituted with a diphtheria-tetanus-acellular pertussis-hepatitis B (DTPa-HBV) vaccine as a three dose primary course at 3, 4 and 5 months of age induced PRP-specific immunological memory, by examining the anti-PRP response to a dose of unconjugated PRP given with the DTPa-HBV booster approximately 1 year later. The unconjugated PRP elicited protective anti-PRP antibody levels (≥?0.15 μg/ml) in all but 3 of the 369 vaccinees, including 13 infants who failed to demonstrate a measurable immune response after the primary course. In a sub-cohort of 54 subjects all had anti-PRP levels ≥?0.5 μg/ml within 7–14 days of the booster showing a rapid anamnestic type response. Both primary and booster responses were predominantly IgG1 indicating a T-cell dependent response. The DTPa-HBV components elicited protective anti-diphtheria, anti-tetanus and anti-HBs antibody levels in ≥?98.5% of vaccinees, and immune responses to each of the acellular pertussis vaccine components in 92.3%–97.3% of subjects. Conclusion?The tetanus-PRP conjugate vaccine not only elicited a good primary humoral response, but also induced immunological memory so that the infants were able to mount a large and rapid immune response to subsequent exposure to plain PRP, indicating that protection against circulating wild-type Hib had been generated. Successful induction of immunological memory occurred even when there was no measurable humoral anti-PRP response to the primary course. Tetanus-PRP conjugate vaccine can be used in combination with DTPa-HBV vaccine, when administered separately or as a single injection in the same syringe, in primary immunisation schedules at 3, 4 and 5 months of age.