Safety and immunogenicity of a bivalent Haemophilus influenzae type b/hepatitis B vaccine in healthy infants. Hib-HB Vaccine Study Group.

OBJECTIVE: To assess the safety, tolerability and immunogenicity of COMVAX, a liquid, bivalent Haemophilus influenzae type b-hepatitis B vaccine, containing the polyribosylribitol phosphate (PRP)-Neisseria meningitidis outer membrane protein complex conjugate used in the Hib vaccine, PedvaxHIB, and the yeast-derived hepatitis B surface antigen (HBsAg) used in the HB vaccine, RECOMBIVAX HB. DESIGN: Eight hundred eighty-two healthy infants, approximately 2 months of age, were enrolled in an open, multicenter (n = 11) clinical trial and randomized to receive either COMVAX (7.5 micrograms of PRP/5 micrograms of HBsAg in 0.5 ml) or concurrent injections of the liquid formulation of PedvaxHIB (P) (7.5 micrograms of PRP in 0.5 ml) and RECOMBIVAX HB (R) (5 micrograms of HBsAg in 0.5 ml) at 2, 4 and 12 or 15 months of age. Safety and tolerability were monitored after each injection. The serum concentrations of anti-PRP and anti-HBs were determined at the time of each vaccination, 2 months after the second vaccination and 1 month after the third vaccination. RESULTS: COMVAX was well-tolerated and proved to be immunologically comparable with a series of concomitant P+R injections. There were no serious adverse experiences attributable to the study vaccines. The most commonly reported nonserious adverse experiences were all events prelisted on diary cards given to parents. These included generally mild and transient signs of inflammation at the injection site (pain/ soreness, erythema, swelling/induration), somnolence and irritability. Because children are at peak risk of invasive Hib disease during the first year of life, 6 months of age (2 months after the second dose of vaccine) was designated the time of primary interest with regard to the development of anti-PRP. At that time 94.8% of the infants given COMVAX had > 0.15 microgram/ml of anti-PRP and 72.4% had > 1.0 microgram/ ml, with a geometric mean concentration (GMC) of 2.5 micrograms/ml, compared with 95.2%, 76.3% and 2.8 micrograms/ml, respectively, in recipients of P+R. The third injection given at 12 or 15 months of age induced a secondary rise in antibody. The proportions with > 0.15 microgram/ml and > 1.0 microgram/ml of anti-PRP increased to 99.3 and 92.6%, respectively, and the GMC rose to 9.5 micrograms/ml among COMVAX recipients, compared with 98.9%, 92.3% and 10.2 micrograms/ml in children given concurrent injections of P+R. In contrast to Hib few infants in countries with low endemicity of HBV infection are at near term risk of exposure to virus. Consequently the anti-HBs response after the last dose of vaccine was designated the outcome of primary interest. At 13 to 16 months of age (1 month after the third dose of vaccine) 98.4% of children given COMVAX had a protective anti-HBs concentration of > or = 10 mIU/ml with a GMC of 4468 mIU/ml, compared with 100% and a GMC of 6944 mIU/ml among children given P+R. CONCLUSIONS: COMVAX is well-tolerated by healthy infants and can induce immunity against invasive Hib disease and HBV infection using only three injections compared with six injections if separate courses of monovalent PedvaxHIB and RECOMBIVAX HB are given.

Safety and immunogenicity of Haemophilus influenzae type B-Neisseria meningitidis group B outer membrane protein complex conjugate vaccine mixed in the syringe with diphtheria-tetanus-pertussis vaccine in young Gambian infants.

To ensure compliance and to reduce costs it is important, especially in less developed countries, that programs of child immunization should require as few clinic attendances and as few injections as possible. Therefore we have investigated whether a Haemophilus influenzae type b conjugate vaccine could be given safely and effectively with diphtheria-tetanus-pertussis vaccine (DTP). One hundred twenty-six Gambian infants were given both polyribosylribitol phosphate (PRP)-outer membrane protein complex (PedvaxHIB) and DTP on the same day at 8, 12 and 16 weeks of age; 60 were given the vaccines mixed in the syringe and 66 were given the vaccines separately. To minimize the injection volume the dose of PRP-OMPC used in both groups was 7.5 micrograms, which is half the usual dose. There were no significant differences in anti-PRP antibody titers between the groups after 1, 2 or 3 doses. The geometric mean titers of antibody for the two groups combined were 0.29 micrograms/ml 1 month after the first dose, 1.03 micrograms/ml after the second dose and 1.11 micrograms/ml after the third dose. Concentrations of antibodies to diphtheria, tetanus and pertussis 1 month after the third dose were not significantly different between the two groups. Systemic side effects were reported with equal frequency in the two groups and were similar to those reported elsewhere for DTP. Tenderness at the injection site was more common where the combined injection (0.75 ml) had been given than where DTP alone (0.5 ml) had been given. The main drawback to the use of these 2 vaccines together is the complexity of the mixing procedure used in this clinical trial.

Anti-PRP antibody levels after a primary series of PRP-OMPC and persistence of antibody titres following primary and booster doses.

The Haemophilus influenzae capsular polysaccharide-outer membrane protein conjugate, PRP-OMPC (PedvaxHIB) elicits very good antibody responses in infants > or = 2 months of age after the first dose. Increasing age at time of first vaccination correlates with higher antibody responses. Anti-PRP responses are consistently high with the first injection among all population groups studied. Booster doses stimulate anamnestic antibody responses after one year of age. Among US children (excluding Navajo and Apache children) given a primary injection at 14-18 months of age, the geometric mean titre (GMT) after 2 to 3 years was > 1 micrograms/ml. US children (excluding Navajo and Apache children) given a primary series at 2 and 4 months of age and a booster at 18 months of age also had an anti-PRP GMT > 1 micrograms/ml 2.5 years later. Navajo and Apache children given a primary series at 2 and 4 months of age and a booster at 12-15 months had antibody levels of 1.50 micrograms/ml one year later. Antibody persistence data suggest there will be long-term protection against Haemophilus influenzae b disease following immunization with PRP-OMPC.

Clinical experience with PedvaxHIB, a conjugate vaccine of Haemophilus influenzae type b polysaccharide--Neisseria meningitidis outer membrane protein.

PedvaxHIB, a Haemophilus influenzae type b (Hib) conjugate vaccine composed of Hib capsular polysaccharide covalently bound to an outer membrane protein complex of Neisseria meningitidis serogroup B, was evaluated for immunogenicity and safety in infants and children 2 months of age and older. A significant and consistent antibody response was seen after a single dose of the vaccine in all age groups, including infants as young as 2 months of age. In addition, the vaccine elicited a good booster response when given at 12 to 17 months of age. Subjects from diverse subpopulations, including those with impaired antibody response to Hib polysaccharide vaccines, showed a significant response to vaccination. The vaccine was well tolerated when administered alone or concurrently with other paediatric vaccines. A protective efficacy study, recently completed, has shown the vaccine to be highly effective in 2-month-old infants.

Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) (PedvaxHIB): clinical evaluation.

Although systemic infections caused by Haemophilus influenzae type b occur worldwide, detailed epidemiologic data are available in but a few countries. The public health impact of morbidity, mortality, and serious sequelae from disease caused by H influenzae type b has stimulated the search for control strategies. In the United States now, active immunoprophylaxis is largely favored over treatment of prophylaxis with antibiotics. This preference stems from three major observations: that high mortality and morbidity persist despite the availability of potent antimicrobial agents, that antibiotic-resistant strains of H influenzae type b have emerged, and that implementation of antimicrobial prophylaxis on a large scale has been unsatisfactory. Moreover, universal vaccination has been projected as offering a higher economic benefit than other control strategies. A matter of more proximate importance, however, is the search for H influenzae type b vaccines that will confer protection to all age groups, including infants younger than 18 months of age and subpopulations specifically at risk for invasive disease caused by H influenzae type b. Haemophilus b conjugate vaccine (meningococcal protein conjugate), PedvaxHIB (PRP-OMPC), is a conjugate H influenzae type b vaccine developed at Merck Sharp & Dohme Research Laboratories that now is undergoing extensive clinical evaluation to assess its prospects for disease control when first administered in early infancy. This is an interim report of results obtained in studies conducted in diverse locations throughout the United States.