The immune response to hepatitis B vaccine in humans: inheritance patterns in families.

Abstract

Sl~1"EllrlaryWe have recently shown that the human antibody response to the hepatitis B virus surface antigen (HBsAg) vaccine is major histocompatibility complex (MHC) associated. In studies of nonresponders to the vaccine, we found an increased incidence of individuals homozygous for human histocompatibility leukocyte antigen (HLA) proteins associated with the extended (conserved) haplotype SC01,DR3]. In later prospective vaccination trials, we showed that none of five individuals homozygous for this haplotype developed more than 1,300 radioimmunoassay (RIA) units of antibody (mean, 467 RIA units), while all heterozygotes made at least 2,500 RIA units (mean antibody level, 15,608 units). Our results suggested that [HLA-B8,SC01,DR3] lacks an immune response gene for HBsAg, and that response is inherited in a dominant fashion. To provide further evidence for this hypothesis, we have now analyzed the results of HBsAg immunization in families. 43 members of 10 families were immunized with the hepatitis B vaccine, including seven families where at least one member bore the haplotype [HLA-BS,SC01,DR3], and three families where one member had already received, but failed to respond to, the vaccine. In two of these three families, the presence of [HLA-BS,SC01,DR3] was subsequently found. Of nine MHC-identical sibling pairs in the study, both members of eight pairs had similar antibody responses (five nonresponder and three responder pairs). In all families with such sibling pairs, including the discordant pair, rank-ordering members by antibody level demonstrated that no relative's value came between the sibling pair values. Furthermore, of nine [HLA-BS,SC01,DR3]-haplotypehomozygous individuals, six were nonresponders, and two others had only low-normal responses.[HLA-BS,SC01,DR3]-heterozygous family members always had higher levels of antibody than their homozygous relatives. Linkage analysis of nonresponse to HLA haplotypes revealed a maximum likelihood LOD (logarithm of the odds) score of 6.3 at a recombination fraction of 0.1. The MHC association with lack of antibody response to HBsAg was not seen with tetanus immunization, where 1 of 20 HBsAg responders and 1 of 21 poor or nonresponders had tetanus titers of <1:512; both tetanus nonresponders were [HLA-B8,SC01,DR3] heterozygotes. Our results indicate that: (a) response to the HBsAg vaccine is MHC linked, and inherited in a dominant fashion; (b) an abnormal or missing immune response (Ir) gene for HBsAg is a characteristic of most examples of the extended haplotype [HLA-B8,SC01,DR3]; and (c) other haplotypes also have abnormal or missing Ir genes for HBsAg.

Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus

“…3, 1999 genetic, or other unknown conditions of hosts may lead to inadequate or restricted immune responses to HBsAg. [68][69][70][71] The large number of reports of S gene mutants associated with unsuccessful perinatal immunoprophylaxis [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] has caused alarm that mutations of amino acids in the a determinant of HBsAg may be a significant cause of vaccine failure. However, molecular epidemiological data from Singapore, 7 Taiwan, 12,16 Indonesia, 14 England and Wales, 17 and the United States 48 have confirmed that, among cases of perinatal vaccine failure, the frequency of infection with S gene mutants is lower than that for infection with wild-type virus.…”

Use of SV40 to immunize against hepatitis B surface antigen: implications for the use of SV40 for gene transduction and its use as an immunizing agent

“…9 However, up to 10% of adults immunized against HBV still fail to respond to the currently used recombinant vaccines. 11 HBsAg is also one of the most suitable markers to test the efficiency of an expression vector in mammalian cells. In vivo, HBsAg synthesis allows straightforward immunochemical detection of HBsAg gene expression in animals.…”

Host genetic factors in hepatitis B infection, liver cancer and vaccination response: A review with a focus on Africa

“…A family based association approach revealed that carriage of the HLA class III C4AQ0 allele lead to non-or slow response to HBV vaccination in Italian subjects (De Silvestri et al, 2001). Work by investigators in the USA showed that with respect to non-response HLA identical siblings were concordant whereas the majority of haplo-or non-identical siblings were discordant, they also presented evidence for linkage with the MHC locus (LOD 6.3) in the families screened (Kruskall et al, 1992).…”