Preparation of Polysaccharide-Conjugate Vaccines (2003)

It was recognized early last century that small molecules, known as haptens, can be made immunogenic after conjugation to carrier proteins (). This principle has since been applied successfully to improve the immunogenicity of (poly)saccharides (,). We now know that the carrier proteins ensure the involvement of T-helper lymphocytes in the activation of the hapten- or polysaccharide-specific antibody-producing B lymphocytes (Fig. 1). In contrast to small molecules or haptens, polysaccharides (or other macromolecules with a repeating structure) are able to induce an immune response, most likely by directly activating B-lymphocytes. Antigens that are able to induce an immune response without the involvement of T-helper lymphocytes are referred to as TI (thymus-independent) antigens () (Table 1). TI-2 antigens, such as plain polysaccharides, are not able to activate relatively immature B-cells. This is in contrast to TI-l antigens, which can activate immature B-cells because of their mitogenic activity. Lipopolysaccharides (LPS) are examples of TI-l antigens. Conventional T-cells recognize peptide sequences in association with the major histocompatibility complex (MHC). Recently, unconventional T-cells were found to recognize (glyco) lipids in a CD1-restricted way, γδT-cells were shown to respond to non-proteinaceous microbial ligands (that may include carbohydrates) in a virtually MHC-unrestricted way (). The findings of T-cell regulation of the immune response against polysaccharides (, , ) without biochemical demonstration of the specificity of the molecular interactions can best be explained by assuming a role for anti-idiotypic antibodies and T-cells specific for the idiotopes (carbohydrate mimotopes) or via the newly discovered unconventional T-cells. Open image in new window Fig. 1. Polysaccharides are poor in activating B-cells to the production of antibodies in children younger than 2 yr of age. If antibodies are formed, they are of short duration. For conjugate vaccines T-cells are involved in the activation of B-cells. Presumably, the conjugate is taken up by polysaccharide-specific B-cells, processed, and presented to carrier-specific T-cells. The involvement of T-cells results in the activation of B-cells to production of antibodies and induction of memory in children younger than 2 yr of age. Table 1 Characteristics of T-Cell Independent Antigens Type 1 Bacterial cell-wall components Mitogenic or polyclonal B-cell activator Stimulate antibody responses in neonates Stimulate antibody responses in CBA/N mice Examples: lipopolysaccharide and hapten derivatives; Brucella abortus Type 2 Polysaccharides, polypeptides, polynucleotides High mol wt, multiple repeating antigenic determinants Slowly metabolized Tolerogenic in large doses or soluble form Activate alternative complement pathway (some) Generate few (if any) memory B-cells Restriction of isotypes induced Lack of affinity maturation Lack of T-cell memory Fail to stimulate antibody responses in neonates Fail to stimulate antibody responses in CBA/N mice Examples: Pneumococcal polysaccharides; Haemophilus influenzaetype b polysaccharide; meningococcal polysaccharides