The effect of reconstitution of an Haemophilus influenzae type b-tetanus toroid conjugate (PRP-T) vaccine on the immune responses to a diphtheria-tetanus-whole cell pertussis (DTwP) vaccine: a five-year follow-up

Controversial results have been obtained from previous studies on the combi ned administration of Haemophilus influenzae type b-tetanus toroid conjugat e (PRP-T) and diphtheria-tetanus-whole-cell pertussis (DTwP) combination va ccines, with regard to possible reciprocal interference between the constit uent antigens. To document the priming effect and possible long-term immuno genic interference of PRP-T and DTwP combination vaccines, a randomized, do uble-blind, controlled study was conducted in Belgium. A total of 168 healt hy infants received, at 3, 4 and 5 months of age, DTwP vaccine mixed just p rior to injection either with PRP-T vaccine (group A, DTwP//PRP-T, N=85) or with placebo (group B, DTwP//Placebo, N-83), Al the age of 14 months, chil dren of both groups were randomized to receive either a dose of DTwP//PRP-T vaccine (subgroups Al and B1) or a dose of Hib polysaccharide (PRP) vaccin e (subgroups A2 and B3). Those children in subgroups Al and B1 had an addit ional serum sample taken at the age of 5 years (at the time of a DT booster ). The immune response to Hib polysaccharide at the age of 4, 5 and 6 months c onfirmed the excellent immunogenicity profile of PRP-T in infants. In addit ion, the vigorous anamnestic response (i.e. a 20-fold increase of GMT) to a booster dose of the plain capsular polysaccharide (PRP) reflected the effi cient Hib-priming induced by the combined DTwP//PRP-T vaccine. Reconstitution of PRP-T with DTwP did not affect the immune response to dip htheria toroid or pertussis agglutinins. Nevertheless, at almost any time p oint during the five-year follow-up, the tetanus antitoxin GMT values were significantly lower in the DTwP//PRP-T group (A and Al) than in the DTwP//P lacebo group (B and B1). Despite the suppressive effect on GMT values, inte rgroup differences in rates of seroprotection were never significant, excep t after doses 2 and 3 for which there were lower percentages of children in group A with antitoxin titers > 0.05 IU/mL and > 1.0 IU/mL. In the group p rimed with the combined DTwP//PRP-T vaccine, (1) a DT booster dose at the a ge of 5 years provoked a 150-fold increase in tetanus antitoxin GMT, (?) a high tetanus antitoxin GMT value was attained (GMT= 19.3 IU/mL) and (3) all children in this group had tetanus antitoxin titers > 1.0 IU/mL, so it may be concluded that all these children will still be protected against tetan us until at least the age of the next recommended booster dose (i.e. the ag e of 15 years). No differences in the occurrence of adverse events were observed between th e groups who received the DTwP//PRP-T vaccine or the DTwP//Placebo vaccine, both vaccines being associated with events customarily attributable to DTw P (data not shown). Our results indicate (1) that the combination vaccine, DTwP//PRP-T, represe nts a safe and effective alternative for the existing uncombined vaccines a nd (2) that the long-term effect of interference between the components of future combination vaccines should be studied with subsequent booster doses , followed by the evaluation of persistence of antibodies over several year s. (C) 1999 Elsevier Science Ltd. All rights reserved.