GENETIC ENGINEERING APPROACHES FOR MALARIA VACCINES

THIS RESEARCH WILL DEVELOP SUBUNIT VACCINES FOR THE TWO PREDOMINANT SPECIES OF MALARIA PARASITES, PLASMODIUM FALCIPARUM AND PLASMODIUM VIVAX. PREVIOUS STUDIES HAVE SHOWN THAT: 1. HYBRID HEPATITIS B VIRUS SURFACE ANTIGEN (HBVSAG) POLYPEPTIDES (COMPOSED OF INSERTIONS OF PART OF THECIRCUMSPOROZOITE GENE OF P. FALCIPARUM INTO THE PRE-S REGIONOF THE HBVSAG GENE) ARE EXPRESSED IN GENETICALLY ENGINEERED YEAST VECTOR SYSTEMS. 2. THESE HYBRID POLYPEPTIDES BECOME MULTIMERIC PARTICLES POSSESSING THE ANTIGENICITIES OF BOTH HBV AND THE MALARIA PARASITE. IN PHASE I, HYBRID HBV POLYPEPTIDES CONTAINING PARTS OF THE CIRCUMSPRORZOITE GENE OF P. VIVAX WILL BE DEVELOPED AND YEAST EXPRESSION VECTORS WILL BE USED TO PRODUCE THE ENTIRE CIRCUMSPOROZOITE PROTEINSOF BOTH MALARIA SPECIES. THE ANTIGENICITY OF THE HYBRID HBVSAG PARTICLES AND CIRCUMSPOROZOITE PROTEINS MADE IN YEASTWILL BE ASSESSED WITH ANTISERA TO THE MALARIA PARASITE. ALSO, HYPERIMMUME HUMAN SERA AND VARIOUS ANIMAL SERA RAISED TO EITHER INTACT PARASITES OR TO SYNTHETIC PEPTIDES REPRESENTING THE REPEAT UNITS OF THE CIRCUMSPOROZOITE ANTIGEN WILL BE TESTED. THE IMMUNOGENICITY OF THESE PREPARATIONS WILL BE EVALUATED IN RODENTS AND IN SUB-HUMAN PRIMATES. THESE STUDIES WILL FOCUS ON MEASURING IMMUNE RESPONSES THAT CORRELATE WITH PROTECTION. THESE PHASE I PROCEDURES-TESTING THE USE OF HYBRID HBVSAG AS A CARRIER FORPRESENTATION OF PORTIONS OF THE CIRCUMSPOROZOITE ANTIGEN ANDTESTING THE ENTIRE CIRCUMSPOROZOITE PROTEIN EXPRESSED IN YEAST-MAY PROVIDE THE MEANS TO AUGMENT THE IMMUNOGENICITY OFTHE SURFACE PROTEINS OF MEROZOITE AND GAMETOCYTE STAGES OF MALARIA PARASITES.