ORAL MALARIA VACCINE DEVELOPMENT IN A PLASMODIUM BERGHEI MODEL

PEPTIDE CARRIER AND RECOMBINANT DNA-PRODUCED PLASMODIUM FALCIPARUM SPOROZOITE SUBUNIT VACCINES HAVE BEEN TESTED IN CLINICAL TRIALS. THESE VACCINES HAVE BEEN DESIGNED TO INDUCE HIGH-TITER PROTECTIVE ANTISPOROZOITE ANTIBODIES. CLINICAL TRIALS HAVE INDICATED THAT THESE VACCINES ARE ONLY PARTLY EFFECTIVE. RECENT STUDIES COMPARED ANALOGOUS PEPTIDE AND RECOMBINANT SUBUNIT VACCINES WITH SPOROZOITE-INDUCED IMMUNITY IN THE PLASMODIUM BERGHEI MODEL.THESE STUDIES SHOWED THAT PARENTERALLY ADMINISTERED P. BERGHEI SUBUNIT VACCINES INDUCE HIGH-TITER SPOROZOITE ANTIBODY THAT IS PARTIALLY PROTECTIVE AT LOW-SPOROZOITE CHALLENGE DOSES. IN CONTRAST, SPOROZOITE-INDUCED IMMUNITY, FULLY PROTECTIVE AT 20 TIMES THE CHALLENGE, IS MEDIATED BY CELLULAR IMMUNITY. THESE PHASE I STUDIES ARE DESIGNED TO EXAMINE THE FEASIBILITY OF IMMUNIZING MICE AGAINST P. BERGHEI SPOROZOITES, A RODENT MALARIA PARASITE, BY ORAL VACCINATION.VACCINATION OF MICE WITH AN ATTENUATED SALMONELLA STRAIN HARBORING PLASMIDS THAT DIRECT THE EXTRACYTOPLASMIC LOCALIZATION OF THE P. BERGHEI CIRCUMSPOROZOITE PROTEIN (CS)IS EXPECTED TO ELICIT NOT ONLY ANTIBODY-MEDIATED BUT ALSO CELL-MEDIATED IMMUNE RESPONSES. THE P. BERGHEI CS GENE WILLBE FUSED TO THE GENE ENCODING THE B SUBUNIT OF THE HEAT-LABILE ENTEROTOXIN OF E. COLI (LTB) AT VARIOUS LOCATIONS, AND THE FUSION PROTEIN WILL BE TESTED FOR IMMUNOGENICITY. IF THESE STUDIES ARE SUCCESSFUL, ANALOGOUS ORAL MALARIA VACCINES COULD BE DEVELOPED FOR HUMANS.