Vaccine- and hepatitis B immune globulin-induced escape mutations of hepatitis B virus surface antigen

Hepatitis B virus surface antigen (HBsAg) vaccination has been shown to be effective in preventing hepatitis B virus (HBV) infection. The protection i s based on the induction of anti-HBs antibodies against a major cluster of antigenic epitopes of HBsAg, defined as the 'a' determinant region of small HBsAg. Prophylaxis of recurrent HBV infection in patients who have undergo ne liver transplantation for hepatitis B-related end-stage liver disease is achieved by the administration of hepatitis B immune globulins (HBIg) deri ved from HBsAg-vaccinated subjects. The anti-HBs-mediated immune pressure o n HBV, however, seems to go along with the emergence and/or selection of im mune escape HBV mutants that enable viral persistence in spite of adequate antibody titers. These HBsAg escape mutants harbor single or double point m utations that may significantly alter the immunological characteristics of HBsAg. Most escape mutations that influence HBsAg recognition by anti-HBs a ntibodies are located in the second 'a' determinant loop. Notably, HBsAg wi th an arginine replacement for glycine at amino acid 145 is considered the quintessential immune escape mutant because it has been isolated consistent ly in clinical samples of HBIg-treated individuals and vaccinated infants o f chronically infected mothers. Direct binding studies with monoclonal anti bodies demonstrated a more dramatic impact of this mutation on anti-HBs ant ibody recognition, compared with other point mutations in this antigenic do main. The clinical and epidemiological significance of these emerging HBsAg mutants will be a matter of research for years to come, especially as data available so far document that these mutants are viable and infectious str ains. Strategies for vaccination programs and posttransplantation prophylax is of recurrent hepatitis need to be developed that may prevent immune esca pe mutant HBV from spreading and to prevent these strains from becoming dom inant during the next decennia.