Background. Meningitis and other invasive infections due to Haemophilus influenzae b (Hib) and pneumococci (Pn) are a major threat to child health. Hib is the most common bacterial agent of meningitis in U.S. children and is fatal to 5-10% and permanently disabling to 30-50% of patients despite therapy. Pneumococci are the second most frequent cause of bacterial meningitis in children (mortality, about 10%), an extreme hazard in sickle cell patients, and the cause of a majority of cases of otitis media. Serum antibodies (Ab) to the capsular polysaccharide (CP) can protect against systemic infections by these bacteria, and the purified CP can be used as vaccines. Immunocompetence to these antigens matures slowly, however, and infants under 2 years old generally do not have a protective response. For Hib, however, anti-CP serum Ab response can be induced in infants by injection of CP-derived oligosaccharides conjugated to a protein carrier. This promising result will be analyzed and extended to the Pn 6, Pn 14, and other poorly immunogenic CPs. Research plan. The Hib conjugate vaccine will be varied in order to examine the relation of immunogenicity to: (a) the state of aggregation, (b) the oligosaccharide chain length, (c) the residue at the non-reducing (free) terminus of the chains, and (d) the multiplicity of chains per protein. A structurally different version of conjugate will be evaluated in which both termini of the oligosaccharide are used to cross-link the proteins. Several different bacterial protein toxoids will be evaluated as carriers. Lymphocyte stimulation in vitro will be used to examine how cellular immunity to the carrier affects the response to saccharide attached to the carrier. The experience gained in the Hib system will be used to prepare immunogenic conjugates versus Pn 6 and Pn 14, pneumococcal types that are the greatest threat in infancy. If progress is rapid, extension to Pn types 18, 19, and 23 would be pursued.
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