Polysaccharide vaccines as probes of antibody repertoires in man

Antibodies specific for capsular polysaccharide epitopes mediate immunity to encapsulated bacterial pathogens, and accordingly, vaccine development has focused upon the induction of these specificities. Efficacious vaccines, consisting of either polysaccharide alone or polysaccharide coupled to protein carriers, have been developed for a number of pathogens. Their clinical importance notwithstanding, these vaccines serve as model antigens to study the genetic and somatic forces molding adaptive immunity in man. In this article we review progress aimed at delineating the structure and dynamics of the human antibody repertoire to the Haemophilus influenzae type b polysaccharide (Hib PS), a system which has been studied from infancy to old age. Collectively, the data reveal a repertoire which is encoded by a relatively large number of germline variable (V) region gene segments, but which is typically expressed within individuals as a markedly restricted, oligoclonal population. One particular V domain has attained canonical status because of its high penetrance at the population level and its predominance in individual repertoires. Although this combining site is assembled in early infancy and retains its prominence throughout life, its frequency of expression, affinity and protective function are dictated by the molecular form of the Hib PS immunogen (vaccine). The determinants of Hib PS binding affinity can include both germline and somatically-acquired V region polymorphisms. We discuss how these properties of the Hib PS repertoire could impact immunity to Hib, and we consider the implications of these findings towards understanding the evolution of immunoglobulin germline V genes.