Multiple Antigen Peptide Vaccines against Plasmodium falciparum Malaria

摘要

The multiple antigen peptide (MAP) approach is an elfective method to chemically synthesize and deliver multiple T-cell and 8-cell epitopes as the constituents of a single immunogen. Here we report on the design, chemical synthesis, and immunogenicity of three PIDsmodium falcipamm MAP vaccines that incorporated antigenic epitopes from the sporozoite, liver, and blood stages of the life cycle. Antibody and cellular responses were determined in three inbred (C5781)(6, BALB/c, and AJJ) strains, one congenic (HLA-Al on the CS7BU6 background) strain, and one outbred strain (CD1) of mice. All three MAPs were immunogenic and induced both antibody and cellular responses, albeit in a somewhat genetically restricted manner. Antibodies against MAP-1, MAP-2, and MAP-3 had an antiparasite effect that was also dependent on the mouse major histocompatibility complex background. Anti-MAP-1 (CSP-based) antibodies blocked the invasion of HepG2 liver cells by P.falciparum sporozoites (highest, 95.16% in HLA-Al CS781)6; lowest, (ll.21% in BALD/c). Furthermore, antibodies generated following immunizations with the MAP-2 (Pf'CSP, PfLSA-1, PfMSP-141, and PfMSP-3h) and MAP-3 (PfRAP-1, PfRAP-2, PfSERA, and PfMSP-141) vaccines were able to reduce the growth of blood stage parasites in erythrocyte cultures to various degrees. Thus, MAP-based vaccines remain a viable option to induce effective antibody and cellular responses. These results warrant further development and preclinical and clinical testing of the next generation of candidate MAP vaccines that are based on the conserved protective epitopes from PIDsmodium antigens that are widely recognized by populations of divergent HLA types from around the world.