McDermott, Adrian B.; (2000) Genetic control of the immune response to antigen: Studies with hepatitis B vaccination. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Genetic predisposition towards antibody nonresponsiveness has been described for many antigens in both man and the mouse model. Approximately 5-10% of healthy individuals receiving licensed hepatitis B vaccines fail to produce protective levels of antibody following standard immunisation protocols. We studied the influence of HLA in 86 true nonresponders (0IU/1) and found an association with HLA-DRBl*0701 (p= 0.001, RR= 3.01) and HLA-DQB1*02 (p= 0.001, RR= 3.08) alleles when compared to 248 controls. Anti-HBs nonresponse was significantly associated with the above alleles when found in linkage disequilibrium on the HLA haplotype HLA-DRB1 *0701; DQB1 *02 (p= 0.001, RR= 3.58). Upon revaccination with a novel hepatitis B vaccine, containing pre-S2, S and immunogenic components of pre-S1 (Hepagene), 30 (35%) vaccinees remained anti-HBs nonresponders of which 21 (70%) expressed the HLA- DRB 1*0701 (p= 0.001, RR= 6.41) and 24 (80%) the HLA-DQB1*02 (p= 0.001, RR= 4.89) alleles. Our results demonstrated the anti-HBs nonresponse to Hepagene was associated with the extended HLA- haplotype B44; HLA-DRB 1*0701; DQB 1*0202 (P= 0.001, RR= 5.80). From linkage disequilibrium analysis we propose that anti-HBs nonresponse is linked to the HLA- DQB1*0202 allele. Further analysis of anti-HBs responses revealed significant differences between dose of Hepagene, HLA haplotype and anti-HBs responses in repeatedly 'S' vaccinated individuals following a single immunisation. Decline in anti-HBs titre between 2-6 months was associated with HLA-DRB1 *0701; DQB 1*0202 male individuals (p= 0.02). Anti-HBs and T-cell kinetics were investigated in vaccinees receiving low dose (5 or 10 g/ml) Hepagene then revaccinated with 20?g/ml after 12 months. These T-cell frequency studies reflected that T-cell responses were associated with kinetics of the response and not the magnitude of the humoral response. Analysis of Hepagene specific T-cell lines generated from vaccinated individuals indicated specificity to both pre-S 1 and pre-S2 peptides from Hepagene. Determination of the cytokine profiles revealed high IFNy, IL-4 but low IL-2 production. We conclude that within this population nonresponsiveness is linked to an inherited trait active upon the T-cell repertoire that underlies hepatitis B vaccine nonresponse.

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