Safety and immunogenicity of combined diphtheria–tetanus–pertussis (whole cell and acellular)–Haemophilus influenzae-b conjugate vaccines administered to Indonesian children

Abstract

A randomized, double-blind trial was conducted to evaluate the safety and immunogenicity of vaccines comprised of diphtheria (D) and tetanus (T) toxoids combined with either a whole cell (P) or an acellular (aP) pertussis component and Haemophilus influenzae type b polyribosylphosphate (PRP)–tetanus toxoid conjugate (PRP–T) in Indonesian infants. Three doses of either DTaP, DTaP–PRP–T, or DTP–PRP–T were administered to 930 infants approximately 2–3 months of age and at 2 month intervals thereafter. A booster dose of either DTP–PRP–T or DTaP–PRP–T was administered at 15–18 months of age. Both local and systemic reactions occurred at a significantly ( p<0.001–0.026) higher rate in the group that received whole cell pertussis vaccine versus groups which were immunized with aP containing vaccines. There was no significant difference ( p>0.05) in the rate of adverse events between groups immunized with DTaP or DTaP–PRP–T. One month after the third dose of vaccine, 99% of subjects had achieved ≥0.1 IU of anti-D and anti-T antibody per ml of serum. The geometric mean titer (GMT) to D was significantly ( p<0.001) higher in the group immunized with DTaP versus the other two groups whereas the anti-T GMT was significantly ( p<0.006) higher for the group immunized with DTP–PRP–T. Both the anti-pertussis toxin (PT) and anti-filamentous hemagglutinin (FHA) antibody levels were significantly ( p<0.001) higher in recipients of acellular versus whole cell pertussis vaccine. In contrast, the anti- B. pertussis agglutinating antibody response was significantly ( p<0.0001) higher in the group immunized with whole cell pertussis vaccine. The anti-PRP GMTs (μg antibody/ml) at 7 months were 0.096, 3.35 and 6.11 for groups immunized with DTaP, DTaP–PRP–T and DTP–PRP–T, respectively. The GMT for those immunized with DTP–PRP–T was significantly ( p<0.001) higher compared to recipients of DTaP–PRP–T. The percent of children who attained ≥0.15 or ≥1 μg/ml after immunization was 18 and 2% for the DTaP group, 93 and 76% for the DTaP–PRP–T group and 97 and 88% for the DTP–PRP–T group. At the ≥1 μg/ml level the difference between the DTaP–PRP–T and DTP–PRP–T groups was significant ( p<0.01). Children immunized with either DTaP, DTaP–PRP–T, or DTP–PRP–T were reimmunized with DTaP–PRP–T whereas a portion of children immunized with DTP–PRP–T where also boosted with this vaccine at 15–18 months of age. There was a vigorous anamnestic response to the D and T components with all children possessing ≥0.1 IU/ml. There was also a substantial increase in anti-PT, anti-FHA and B. pertussis agglutinating antibodies. The poorest anti-PT response was seen among children receiving DTP–PRP–T for both primary and reimmunization while the highest agglutinating antibody response followed receipt of 4 doses of DTP–PRP–T. Greater than 80% of children immunized with either DTP–PRP–T or DTaP–PRP–T possessed ≥0.15 μg/ml before boosting versus 38% for those vaccinated with DTaP ( p<0.001). Primary immunization with DTP–PRP–T resulted in a significantly ( p<0.05) higher percentage (72%) maintaining ≥1 μg/ml compared to those immunized with DTaP–PRP–T (46%). Prior to reimmunization, the anti-PRP GMT was significantly ( p<0.005) higher for children immunized with 3 doses of DTP–PRP–T versus DTaP–PRP–T. Subsequent to reimmunization, ≥95% of subjects attained ≥1 μg/ml.