Evaluation of vaccines in infancy. With special reference to Haemophilus influenzae type B conjugates

Abstract

During the 1990s, two new vaccines have been introduced in the national Swedish vaccination programme; Haemophilus influenzae type b (Hib) conjugate vaccine in 1993 and acellular pertussis vaccine in 1996. In the pre-vaccination era, Hib caused nearly 50% of all cases of bacterial meningitis in children, and almost all cases of acute epiglottitis. Already in 1994, a dramatic decline in the incidence of invasive Hib disease was noted and after 1996 also in the incidence of pertussis.The immunogenicity and safety of vaccines against Hib, diphtheria, tetanus, polio and pertussis, administered to 669 Swedish infants, were evaluated in three vaccination studies. The trials involved 2,085 scheduled vaccination visits and 2,340 blood sampling visits. The aims were to compare two Hib conjugate vaccines, Hib conjugated to tetanus toxoid (Hib-T) or a meningococcal outer membrane protein (Hib-OMP), to evaluate the antibody response to the tetanus toxoid component of Hib-T, to study the influence of a concurrent dose of the tetanus toxoid on the Hib antibody response of Hib-T, to compare administration routes and to compare a 3-5-12 month schedule with a 2-4-6-13 month schedule. Serum antibodies against all vaccine components were analysed and adverse reactions were monitored. In two additional studies the natural acquisition of serum antibodies to Hib and to two components, FHA and pertactin, included in some aP vaccines, were followed from infancy to school age. Serum levels of Hib antibodies of the IgG1, IgG2 and IgG4 subclasses in non-vaccinated healthy children were compared with those in children vaccinated in infancy with a Hib conjugate vaccine.The tetanus toxoid component of Hib-T induced functional antibodies against tetanus, but at a lower magnitude than the ordinary tetanus toxoid vaccine. The two Hib conjugates induced lower than expected concentrations of Hib antibodies after the first two injections, but the proportions of infants with antibodies above proposed protective level were satisfactory. The antibody response to the booster dose of Hib-T was excellent, demonstrating a good priming effect from the first two doses. Mixing of Hib-T with diphtheria, tetanus, polio and aP vaccines did not negatively influence the Hib antibody response, and a concurrent dose of tetanus toxoid did not enhance the Hib antibody response to Hib-T. The concentrations of antibodies to the other antigens were good and similar also when the vaccines differed in antigen amounts. The concentrations of antibodies against all vaccine components were lower after two than after three primary dosese, but were equally high after the booster dose. Subcutaneous administration of vaccines did not affect the antibody responses, but caused more local reactions than intramuscular administration. The adverse reactions were mild and well tolerated. In summary, the trials documented the use of the vaccines and combinations tested in the present Swedish national vaccination programme, with adequate immune responses from all components in the 3-5-12 months schedule. The immunogenicity of the protein carrier may become of clinical significance in future programmes, likely to include new conjugate vaccines under developmentPre-school children with no pertussis infection or vaccination had acquired low levels of antibodies against FHA and pertactin. It remains unclear whether or not natural acquisition of such antibodies can contribute to protection. Children vaccinated in infancy with a Hib conjugate had similar concentrations of different Hib IgG subclasses at six years of age as compared to non-vaccinated healthy controls, who by this age normally have acquired protective Hib antibodies naturally, indicating that a Hib conjugate given during the first year of life confers protection until acquisition of a natural immunity.