Overview

Molecular Basis of Humoral Immunity to Encapsulated Pathogens
The prevention of many serious infectious diseases by vaccination represents a major public health and biomedical achievement of the twentieth century. However, these advances are based largely on empirical observations; a clear mechanistic understanding of how vaccines elicit protective immunity is not understood.

Dr. Lucas conducts a program that seeks to elucidate the molecular basis of human humoral immunity to a class of bacterial pathogens that are covered with a polysaccharide capsule. Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae are two encapsulated bacteria being studied by the Lucas group. These two organisms cause serious infections, particularly in children. Antibodies directed against the capsular polysaccharides protect against infection, and pediatric vaccines incorporating these polysaccharides have been developed. Lucas and his colleagues observed that the anti-polysaccharide antibodies elicited in infants by different Hib vaccines are not functionally equivalent. Some Hib vaccines induce antibodies that bind the capsular polysaccharide with greater affinity than antibodies induced by other Hib vaccines. Their studies have shown that these differences in anti-Hib polysaccharide antibody affinity profoundly affect antibody protective efficacy against Hib infection, and more recently, they have extended this observation to antibodies against pneumococcal polysaccharides.

Lucas and his colleagues are determining the primary structures of anti-Hib and anti-pneumococcal polysaccharide antibodies. These analyses permit them to identify the genes encoding these antibodies, and to map the structural determinants of polysaccharide binding affinity. They have found that subtle differences in amino acid sequence can drastically impact antibody binding affinity and consequently protective efficacy. Amino acid sequence polymorphisms are acquired during antibody gene assembly, during the process of somatic hypermutation that is elicited by vaccination, and by direct encoding in the germline. These studies have defined both genetic (inherited) and somatic (acquired) mechanisms of humoral immunity to encapsulated pathogens. Lucas and his colleagues are trying to discern the relative contributions that these mechanisms play in determining susceptibility to developing invasive disease. In addition, they are testing the hypothesis that Hib vaccines differentially promote antibody gene mutation, and therefore, elicit antibodies with disparate affinities. Thus, Lucas and his colleagues use polysaccharide vaccines as probes to investigate the molecular diversity of protective antibody repertoires. Their studies will help unravel the evolutionary and somatic forces shaping human immunity and may enable the design of more effective vaccines.