An effective vaccine against malaria represents a high priority development task. Plasmodium falciparum, the causative agent of malaria, is a complex, multi-stage pathogen, targeted by distinct immune mechanisms. Protective immunity can be induced by immunization by intact parasite, but no subunit vaccine that induces protection comparable to that induced by the whole organism is available. We suggest that a vaccine focused on sequences encoding those minimal epitopes considered important in protection, and eliminating sequences with no apparent role in protection, will be more immunogenic and protective in a broader population range than vaccines based on a single antigen is available. Accordingly, we propose to design and optimize a multi-epitope based malaria vaccine comprising 26 CTL and 13 HTL epitopes from P. falciparum. These epitopes have been selected such that they are recognized in the context of multiple HLA alleles representative of those most commonly expressed worldwide, with a population coverage estimated to exceed 95 percent for Class I and 85-99 percent for Class II in each of the 5 most prevalent ethnicities. Further, the epitopes are conserved amongst parasite strains sequenced to date. Finally, the criteria for optimal design of multi-epitope vaccines established here, using the complex P. falciparum parasite as a model system, could be rapidly extrapolated to other pathogens of viral and bacterial origin. PROPOSED COMMERCIAL APPLICATION: The overall focus of our research is to develop a vaccine for prevention of malaria caused by Plasmodium falciparum. No vaccine to prevent malaria is currently available.