title: Immunity to malaria elicited by hybrid hepatitis B virus core particles carrying circumsporozoite protein epitopes.
abstract: The hepatitis B virus (HBV) nucleocapsid antigen (HBcAg) was investigated as a carrier moiety for the immunodominant circumsporozoite (CS) protein repeat epitopes of Plasmodium falciparum and the rodent malaria agent P. berghei. For this purpose hybrid genes coding for [NANP]4 (C75CS2) or [DP4NPN]2 (C75CS1) as internal inserts in HBcAg (between amino acids 75 and 81) were constructed and expressed in recombinant Salmonella typhimurium. The resulting hybrid HBcAg-CS polypeptides purified from S. typhimurium were particulate and displayed CS and HBc antigenicity, however, the HBc antigenicity was reduced compared to native recombinant HBcAg. Immunization of several mouse strains with HBcAg-CS1 and HBcAg-CS2 particles resulted in high titer, P.berghei- or P.falciparum-specific anti-CS antibodies representing all murine immunoglobulin G isotypes. The possible influence of carrier-specific immunosuppression was examined, and preexisting immunity to HBcAg did not significantly affect the immunogenicity of the CS epitopes within HBcAg-CS1 particles. Similarly, the choice of adjuvant did not significantly alter the immunogenicity of HBcAg-CS hybrid particles. Immunization in complete or incomplete Freund's adjuvant or alum resulted in equivalent anti-HBc and anti-CS humoral responses. Examination of T cell recognition of HBcAg-CS particles revealed that HBcAg-specific T cells were universally primed and CS-specific T cells were primed if the insert contained a CS-specific T cell recognition site. This indicates that the internal site in HBcAg is permissive for the inclusion of heterologous pathogen-specific T as well as B cell epitopes. Most importantly, 90 and 100% of BALB/c mice immunized with HBcAg-CS1 particles were protected against a P. berghei challenge infection in two independent experiments. Therefore, hybrid HBcAg-CS particles may represent a useful approach for future malaria vaccine development.
authors.affiliation: Department of Bacterial Diseases, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
authors.forename: F
authors.initials: F
authors.lastname: Schödel
authors.forename: R
authors.initials: R
authors.lastname: Wirtz
authors.forename: D
authors.initials: D
authors.lastname: Peterson
authors.forename: J
authors.initials: J
authors.lastname: Hughes
authors.forename: R
authors.initials: R
authors.lastname: Warren
authors.forename: J
authors.initials: J
authors.lastname: Sadoff
authors.forename: D
authors.initials: D
authors.lastname: Milich
mesh_terms: D000818:Animals; D001483:Base Sequence; D000939:Epitopes / Q000032:analysis*; D005260:Female; D006512:Hepatitis B Core Antigens / Q000276:immunology*; D007114:Immunization; D008288:Malaria / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D016052:Protozoan Vaccines / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000939:Epitopes; D006512:Hepatitis B Core Antigens; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; C041595:circumsporozoite protein, Protozoan