Variants of two major T cell epitopes within the hepatitis B surface antigen are not recognized by specific T helper cells of vaccinated individuals

Abstract

H epatitis B is a worldwide problem and a major health issue.Approximately 350 million people are carriers of hepatitis B virus (HBV) and more than one million die each year due to acute fulminant disease or the sequelae of chronic hepatitis, manifested as cirrhosis and primary hepatocellular carcinoma. 1 Vaccination is the most important prophylactic measure for the control of this infection. Hepatitis B vaccines produced from plasma of chronic carriers of the virus or through genetic engineering of recombinant yeast or animal cells have been shown to be highly immunogenic, effective, and safe. 2 Universal vaccination, initially recommended only for highly endemic areas, has now been proposed for all countries, because it has become clear that only worldwide vaccination will be able to significantly reduce the burden of this epidemic and could finally lead to the eradication of its causative agent. 3 The success of this strategy, however, has now been challenged by the recent discovery of mutant hepatitis B viruses showing amino acid exchanges in their surface protein hepatitis B surface antigen (HBsAg), which might lead to reduced or even abolished binding of vaccine-induced neutralizing antibodies. 4 Several of such "escape mutants" have been described so far, all showing changes in the so-called "a" determinant of HBsAg, which is assumed to be the main target for neutralizing antibodies. [5][6][7][8][9] However, there is so far no indication that these mutants play a role epidemiologically, and up to now, no proven case of a successfully vaccinated individual infected by such a mutant has been described. Nevertheless, there is considerable interest in the further investigation and characterization of HBV variants. Recent studies have shown that HBsAg is more variable than initially thought, and amino acid exchanges are scattered over the whole molecule. Thus, the T-cell epitopes of HBsAg being targets for recognition by T-helper cells should also be affected. However, little is known so far about the nature and frequency of such mutations or about the possible impairment of the interaction of specific T cells with the changed epitopes. We therefore looked for variations in the sequences of the 4 T-helpercell epitopes of vaccine-type HBsAg and analyzed healthy individuals vaccinated against hepatitis B for their T-cell responses against these variant sequences. interferon gamma; interleukin 4; MHC, major histocompatibility complex. Materials and Methods Donors

Coexistence of Hepatitis B Surface Antigen (HBs Ag) and Anti-HBs Antibodies in Chronic Hepatitis B Virus Carriers: Influence of “a” Determinant Variants

“…Although it seems quite convincing that these changes may alter antibody recognition of the S protein, very little is known about the consequences of such modifications on T-cell epitope recognition. As recently described by Bauer et al for vaccines, accumulations of changes in CHB patients' T-helpercell epitopes may also alter immune response efficacies and may facilitate virus persistence (4).…”

Pathogenesis of hepatitis B virus infection

“…Further studies are needed to address this issue. In addition to immune escape on the B cell level, vaccine escape mediated by defined HBsAg epitopes can occur on the T cell level [61] . Taken together, these findings indicate, that careful epidemiologic monitoring of vaccine failure caused by infection with HBV mutants may be crucial for the success of global immunization strategies.…”

Unusual Naturally Occurring Humoral and Cellular Mutated Epitopes of Hepatitis B Virus in a Chronically Infected Argentine Patient with Anti-HBs Antibodies

“…Moreover, as observed in Fig. 3, two clones exhibited amino acid exchanges in class II T helper epitopes (positions 136 to 155) (2), as were I152F and P153T, while 5 clones showed the I213L replacement in another class II T-cell epitope (positions 213 to 226) (2).…”

“…49 and 152 to 213 of the S protein, were also described, thus affecting several B-cell and major histocompatibility complex class I (MHC-I) and MHC-II T-cell epitopes that might be associated with viral persistence (2,8,14,24,30,36).…”