HEPATITIS-B VIRUS CORE AND E-ANTIGEN - IMMUNE RECOGNITION AND USE AS A VACCINE CARRIER MOIETY

The hepatitis B virus (HBV) core gene codes for two partially colinear antigens: a secreted antigen (HBeAg) and the particulate core antigen (HBcAg), which assembles to form subviral particles and in virions co ntains the viral genome and polymerase, In this review we summarize da ta on the immune recognition of HBc/eA and recent progress in the use of HBcAg as a carrier moiety for heterologous epitopes. During HBV inf ection, HBcAg and HBcAg are important targets of antiviral immunity, H BcAg and HBeAg are serologically distinct but share all characterized T-cell epitopes. The particulate HBcAg can elicit T-cell-independent a s well as T-cell-dependent antibody responses. HBeAg is a strictly T-c ell-dependent antigen. Neonatal tolerance to maternally derived circul ating HBcAg may facilitate chronic HBV infection after vertical transm ission of HBV. In a murine transgenic model, HBc/eAg-specific Th1 cell s were more readily anergized, whereas Th2 cells more easily escaped t olerization, In human HBV infection, acute adult HBV infection with su bsequent virus elimination was characterized by Th1-like alpha-HBV ser um Ige subtype distribution, whereas a Th2-like distribution of IgG su btypes was observed during chronic infection. During chronic infection , core gene mutants which abolish HBeAg synthesis were frequently obse rved. To exploit the unusual immunogenicity of particulate HBcAg as a vaccine carrier moiety, insertion sites for foreign epitopes were defi ned in recombinant expression systems, While fusion of epitopes to the N-terminus required a linker sequence for surface accessibility both fusion to the N-terminus and to the C-terminus was compatible with par ticle assembly and preserved the native antigenicity and immunogenicit y of HBcAg. Epitope insertion at an immunodominant internal site of HB cAg reduced the HBcAg immunogenicity and antigenicity and most drastic ally enhanced the immunogenicity of the inserted foreign epitopes. Thi s internal site of HBcAg was used to express circumsporozoite antigen (CS) repeat epitopes of two rodent malaria parasites and of Plasmodium falciparum. Purified hybrid HBcAg-CS proteins were particulate and di splayed CS antigenicity as well as reduced native HBc antigenicity. Im munization of several mouse strains with HBcAg-CS hybrid particles res ulted in high-titered serum anti-CS antibodies representing all murine IgG isotypes and protected BALB/c mice against plasmodial challenge, immunization of mice with HBcAg or HBcAg-CS particles formulated on al um, complete Freund's or incomplete Freund's adjuvant resulted in equi valent anti-CS and anti-HBc serum antibody titers, Preexisting immunit y to HBcAg did not significantly alter the immunogenicity of hybrid HB eAg particles suggesting that carrier-specific immune suppression does not limit the use of hybrid HBcAg with internal insertions, Immunizat ion with HBcAg-CS particles universally primed HBcAg-specific T cells and in addition CS-specific T cells were if the insert contained a CS- specific T-cell site for the corresponding murine MHC class II haploty pe. The internal amino acid position in HBcAg is therefore permissive for the inclusion of heterologous T-helper as at ll as B-cell epitopes .