Autoimmunity Reviews 2 (2003) 248–257 1568-9972/03/$ - see front matter  2003 Elsevier Science B.V. All rights reserved. PII:S1568-9972 ( 03 ) 00031-4 Immunogenetics of the response to HBsAg vaccination David R. Milich *, Geert G. Leroux-Roels a, b The Vaccine Research Institute of San Diego, Department of Immunology, San Diego, CA 92109, USA a Center for Vaccinology, Department of Clinical Biology, Microbiology and Immunology, Ghent University Hospital, b De Pintelaan 185, 9000 Ghent, Belgium Accepted 29 January 2003 Abstract The major envelope protein of the hepatitis B virus (HBV), the HBsAg, constitutes the current preventative vaccine, which represents the first subunit viral vaccine developed. The genetics of the immune response to HBsAg has been extensively studied both in humans and mice. Murine studies begun over 20 years ago indicated that at least two MHC class II and one MHC class III genes regulate anti-HBs immune responses. Additional MHC-linked genes influence the immune responses to the higher molecular weight (pre-S) components of the HBV envelope. The murine studies predicted even more complex MHC gene regulation of human immune responses to the HBsAg and that complexity certainly has been demonstrated during the ensuing years. This brief review is an attempt to summarize our current understanding of the MHC genes that influence the immune response to the HBsAg and possible mechanisms of action.  2003 Elsevier Science B.V. All rights reserved. Keywords: Hepatitis B surface antigen; Immunogenetics; Major histocompatibility complex; Vaccine The major envelope protein of the hepatitis B virus (HBV), the HBsAg, has been extensively studied as an immunogen in mice and as a preven- tative vaccine in humans. This has provided a unique opportunity to examine the genetic influ- ences on the immune responses to the same antigen in mice and man. 1. Murine studies Early studies in mice indicated marked strain variation in anti-HBs antibody production after *Corresponding author. 3030 Bunker Hill Street, Suite 300, San Diego, CA 92109, USA. Tel.: q1-858-581-3960; fax: q 1-858-581-3970. E-mail address: dmilich@vrisd.org (D.R. Milich). immunization with HBsAg w1x. Further studies in mice that were genetically identical except within the MHC indicated a strong influence of MHC- linked genes on the immune response to HBsAg and identified high (H-2 ), intermediate (H-2 ) d,q a H-2 )H-2 ), and lowynon-responder (H-2 ) b k s,f MHC genotypes w1,2x. The HBsAg is a particulate antigen possessing a group-specific B cell epitope, designated a, and two sets of subtype-specific antibody epitopes, dyy and wyr. 2. Influence of MHC class II and class III genes Studies in intra-H-2 recombinant, congenic strains defined the influence of MHC class II genes on the immune response to distinct antigenic