Genetic Prediction of Nonresponse to Hepatitis B Vaccine

• Published in: The New England journal of medicine Vol. 321; no. 11; pp. 708 - 712
• Main Authors: Alper, Chester A, Kruskall, Margot S, Marcus-Bagley, Deborah, Craven, Donald E, Katz, Aubrey J, Brink, Stuart J, Dienstag, Jules L, Awdeh, Zuheir, Yunis, Edmond J
• Format: Journal Article
• Language: English
• Published: Boston, MA Massachusetts Medical Society 14.09.1989
• Subjects: Adolescent; Adult; Antibody Formation; Antibody response; Biological and medical sciences; Child; Child, Preschool; Chromosomes; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genes, MHC Class II; Genetic Linkage; Genetics of the immune response; Haplotypes; Hepatitis B; Hepatitis B - immunology; Hepatitis B Antibodies - analysis; Hepatitis B surface antigen; Hepatitis B Vaccines; Heterozygote; Heterozygotes; Histocompatibility antigen HLA; Homozygote; Homozygotes; Humans; Immunobiology; Major Histocompatibility Complex; Prospective Studies; Radioimmunoassay; Time Factors; Vaccination; Vaccines; Viral Hepatitis Vaccines - immunology; Human; HLA-System; Hepatitis B surface antigen; Immune response; Major histocompatibility system; Inheritance; Vaccine; Infection; Virus; Viral hepatitis B; Immunogenetics; Gene; Hepadnaviridae; Viral disease; Hepatitis B virus; Haplotype; Humoral immunity
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJM198909143211103

In previous studies of the antibody response to hepatitis B vaccine in 598 subjects who received a full course of vaccination, we observed a bimodal response, with about 14 percent producing less than approximately 1000 radioimmunoassay (RIA) units. An analysis of the major histocompatibility complex (MHC) HLA and complement types of 20 of the subjects with the lowest responses indicated a greater-than-expected number of homozygotes for the extended or fixed MHC haplotype [HLA-B8,SC01,DR3]. This finding suggested that the lack of a normal response was a recessive MHC-linked trait. In this study, we prospectively vaccinated five homozygotes and nine heterozygotes for this haplotype in the expectation that the homozygotes would produce much lower levels of antibody than the heterozygotes. When the antibody response was assessed two months after the third injection, four of the five homozygotes had produced very low levels (approximately 1000 units or less) of antibody (mean, 467 RIA units; range, <8 to 1266), whereas all nine heterozygotes produced more than 2500 RIA units (mean, 15,608; range, 2655 to 28,900) (P<0.01). We conclude that the usual response to hepatitis B surface antigen is due to the presence of a dominant immune-response gene in the MHC and that a low response is due to the absence of such a gene and the presence on both chromosomes of MHC haplotypes (such as [HLA-B8,SC01,DR3]) that indicate such a response. (N Engl J Med 1989;321:708–12.) THE ability to produce antibody in response to specific protein antigens has been shown to be controlled by autosomal dominantly expressed Class II genes of the major histocompatibility complex (MHC) in mice and other species. 1 The demonstration of such genes in humans has been difficult. Although synthetic amino acid terpolymers have been very useful in delineating such genes in laboratory animals, applications to the analysis of the genetic determinants of the immune response in vitro have been difficult in humans 2 and have yielded somewhat different results in different laboratories. 3 , 4 The results have suggested the presence of dominant immune-response genes within . . .