Hepatitis B is a major worldwide cause of morbidity and mortality. Although a vaccine based on the major viral surface protein, HBsAg, protects most immunized subjects, about 4 percent of the population fails to respond. The objective of the proposed research is to understand the mechanisms of the immune response and of the failure of response to the major surface antigen of the hepatitis B virus, HBsAg. The extent to which the response is genetically controlled will be defined by immunizing identical twins and their immediate family members and comparing their response with that of major histocompatibility complex (MHC)- identical siblings. From the study of these and other families and from studies of the response in vitro, the major T-cell epitopes of HBsAg will be defined and the response or nonresponse to them will be correlated with specific MHC alleles and fixed, extended haplotypes. The relationship between T-cell antigen receptor (TCR) Valpha and Vbeta gene and sequence usage and specific MHC alleles and extended haplotypes will be defined in responders and nonresponders to HBsAg. TCR V genes and sequences onT-cells proliferating in response to whole HBsAg as well as to individual epitopes will be compared with the overall repertoire of the same responders before boosting and with that of nonresponders. Other studies will explore whether the defect in nonresponders is in antigen presentation or inT-cell function, including cytokine production. The investigators have preliminary evidence that they can measure a primary response to HBsAg in vitro. They will apply this assay to immunized individuals and then immunize them to determine if the in vitro tests predicts the response in vivo. They will also use the assay to determine the extent to which nonresponse results from anergy or deletion of responsive T-cell precursors.
