Variable immune responses to hepatitis B virus (HBV) infection and recombinant HBV vaccines have been associated with polymorphisms in several genes within the human leukocyte antigen (HLA) complex. Analyses of polymerase chain reaction (PCR)-based genotyping data from 164 North American adolescents vaccinated with recombinant HBV products confirmed that HLA-DRB1*07 (relative odds [RO] β«Ψβ¬ 5.18, P < .0001) and human immunodeficiency virus type 1 (HIV-1) infection (RO β«Ψβ¬ 3.91, P < .001) were both associated with nonresponse to full-dose vaccination. Further associations were observed with single nucleotide polymorphisms (SNPs) at the IL2 and IL4 loci along with insertion/ deletion variants at the IL12B locus (P β«Ψβ¬ .003-.01). Host genetic associations were independent of one another as well as other HLA (A, B, C, and DQB1) and cytokine gene (IL4R, IL6, IL10, and TNF) variants. Statistical adjustments for nongenetic factors (gender, ethnicity, age, HIV-1 infection, and vaccination protocols) did not substantially alter the strengths of the genetic relationships. The overall distribution pattern of genetic variations was similar between the analyzed vaccinees and additional adolescents (n β«Ψβ¬ 292) from the same cohort. In conclusion, DRB1*07 (or a closely linked allele) and immunoregulatory cytokine gene polymorphisms correlate with variable immune response to recombinant HBV vaccines. (HEPATOLOGY 2004;39:978 -988.)
C hronic hepatitis B virus (HBV) infection affects 350 million people worldwide and is the leading cause of liver cirrhosis and hepatocellular carcinoma. 1,2 Vaccination for HBV infection has been highly successful, 3 but immune responses to multidose HBV vaccines vary from individual to individual. At least 5% to 10% of most healthy adult populations fail to produce protective levels of antibodies to recombinant HBV surface antigen (HBsAg) following standard vaccination protocols. 4 -6 HLA diversity may account in part for selective suboptimal HBV antigen presentation, 5,7,8 while epidemiologic and experimental studies have also documented interindividual differences in other measures of immunity, including magnitude of the HBsAg-specific T cell response, 9 breadth of the B cell repertoire, 10 and intensity of T-helper (T H ) type 1 (T H 1) and 2 (T H 2) cytokine secretion. [11][12][13] Several markers in the HLA region have been associated with responder and nonresponder phenotypes following full-dose HBV vaccination. 5,7,8,14 -17 Other candidate genes, especially those encoding immunoregulatory cytokines, may further modulate these differential responses. Potential effects of cytokine genes encoding interleukin (IL)-2 and IL-12 deserve special attention, because recombinant forms of these molecules are increasingly used as immune adjuvants in animal and human vaccine studies. In a cohort of North American adolescents, we detected multiple independent associations of HLA class II as well as T H 1 and T H 2 cytokine gene variants with differential responses to full-dose HBV vaccination.