Chemically modified capsular polysaccharides as vaccines.

Abstract

Capsular polysaccharides have assumed an important role as vaccines against disease caused by bacteria in humans. The concept of using pure definable polysaccharides devoid of their accompanying complex bacterial mass is technically elegant and is obviously capable of extension into other areas of immunoprophylaxis. However, problems have been identified which will need to be solved in order that the concept may be more widely adopted. Focusing on the meningococcal polysaccharides, possible solutions to two of these important problems, namely, the poor immunogenicity of the A and C polysaccharides in infants, and the poor immunogenicity of the B polysaccharide in all humans, are proposed. These solutions involve the use of a new generation of artificial synthetic antigens for modulating the immune response. For instance, conjugation of the A and C polysaccharides to tetanus toxoid converted them to T-cell dependent antigens in mice, thus making these conjugates potential infant vaccine candidates. Although a similar conjugation of the B polysaccharide failed to substantially enhance its immunogenicity in mice, this could be achieved by further chemical manipulation of the basic structure of the B polysaccharide. N-propionylation of the B polysaccharide, followed by its conjugation to tetanus toxoid, yielded an antigen, which when injected in mice, induced in them high titers of cross-reactive B polysaccharide-specific IgG antibodies. The chemical modification of polysaccharides requires an understanding of the interrelation between their structures and immunospecificities, and the structural elucidation of polysaccharides and the resultant monitoring of their structural modifications, can be conveniently accomplished using a wide range of NMR spectroscopic techniques. The capsular polysaccharides of many of the bacteria which cause meningitis in humans contain sialic acid and have extensive structural homology with human tissue. As a result of this homology the immunospecificities of these polysaccharides are complex, being based on unconventional conformational determinants.