Responsiveness of infants to capsular polysaccharides: Implications for vaccine development

Antibodies directed to capsular polysaccharides form an essential component in the defence against infections with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae type b. The antibody response to polysaccharide antigens can occur in the absence of a functional thymus, and these antigens are therefore designated thymus-independent. However, regulatory T cells may and do influence the magnitude of the antibody response to capsular polysaccharide antigens. So-called thymus-independent type 2 antigens share several features of their immune response, such as late development of antibody synthesis in ontogeny, no memory formation and a restricted isotype (IgM, IgG2) and idiotype usage. In infants and young children up to the age of 2 years the antibody response to capsular polysaccharides is inadequate, resulting in an increased incidence of diseases such as pneumonia, meningitis, otitis and other forms of bacterial infection. Though antibodies to polysaccharide antigens in young children are mainly of the IgM and IgG1 (IgG3) isotype, in older children and adults the anti-polysaccharide antibodies are predominantly localized in the IgG2 subclass. The bridge between IgG2 type antibodies and phagocytosis of encapsulated bacteria is constituted by Fcγ receptors for IgG2 on effector cells. The recent finding that allotypes of FcγRIIa either bind or do not bind IgG2 type antibodies strongly suggests that the defence of a given individual to encapsulated bacteria, apart from an intact antibody formation and the complement system, is also determined by the allotype of the appropriate Fcγ receptor. Prevention of disease by encapsulated bacteria can be achieved by vaccination with polysaccharide-protein conjugates which convert the thymus-independent type 2 nature of the antigen to a thymus-dependent nature, implying development of B cell memory, localization of antibodies in other Ig isotypes and affinity maturation of the antibody response. The use of conjugate vaccines for H. influenzae has been proven to reduce dramatically the occurrence of invasive infections in infancy. Apart from knowledge on the efficacy of conjugate vaccines, it can be expected that the application will also give more insight into the mechanism of defective antibody formation to polysaccharide antigens.