Background: Malaria is the number one infectious disease threat facing the US soldier, and it is the leading cause of all casualties during tropical deployments. The military has established a goal for malaria vaccine efficacy: prevent malaria infection for 6 months in at least 80% of vaccinees and limit disease among individuals who do become infected. Existing models of immunity indicate that an effective vaccine is feasible. Immunity that prevents disease develops in naturally exposed populations and is passively transferred in the IgG fraction of serum. The proteins targeted by the immune responses that mediate protection from severe malaria have not been identified; therefore, the optimal antigens for inclusion in a malaria vaccine for soldiers remain unknown. We have identified parasite forms that cause severe disease in Tanzanian infants.

Objective/Hypothesis: We hypothesize that the antigens targeted by protective immune responses in the known models of immunity can form the basis for an effective vaccine for soldiers. We have identified a parasite form infecting infants with severe anemia, and recent scientific and technological advances have made it feasible to identify the surface antigens expressed by these parasites.

Specific Aims: Our specific aims are to identify and prepare the parasite forms causing severe anemia and then apply functional genomics and bioinformatics tools to identify 15-30 proteins that could form the basis for an effective vaccine at both the pre-erythrocytic and blood stages of malaria infection. We will subsequently evaluate these lead candidates in the immunoepidemiologic studies in order to identify the leading 3-5 candidates for a blood-stage vaccine that prevents severe malaria.

Study Design: Our program has the following technical objectives in order to test our hypothesis and the following outcomes upon achievement of these objectives.

(1) Prepare and characterize the phenotype-specific forms of the malaria parasite that are targeted by protective immunity. Outcomes: Identify and prepare the forms of the blood-stage parasite that cause severe malaria. (2) Perform transcriptome analysis of parasites targeted by protective immunity. Outcomes: Identify gene transcripts that distinguish parasites causing severe malaria from other blood-stage parasites. (3) Analyze the proteome of parasites targeted by protective immunity. Outcomes: Identify the surface proteins of blood-stage parasites causing severe malaria. (4) Select proteins and epitopes as vaccine candidates. Outcomes: Apply bioinformatics tools that integrate microarray and proteomics studies and that analyze protein features for vaccine antigen selection. (5) Validate vaccine antigen candidates in models of protective immunity. Outcomes: Identify the surface antigens of blood-stage parasites targeted by protective antibodies.

Relevance: These studies will test the hypothesis that the optimal antigens for an effective malaria vaccine can be identified using knowledge of naturally occurring immunity and functional genomics tools. The proteins targeted by the immune responses that mediate protection have not been identified; therefore, the optimal antigens for inclusion in a vaccine for soldiers remain unknown. We are identifying the parasite forms that cause specific severe malaria syndromes and have found that Tanzanian infants with severe or moderate anemia are infected with parasites that bind ELAM or P selectin. A vaccine to prevent severe malaria should target the surface proteins of these parasites that are targeted by naturally acquired protective immunity. These studies will identify the antigens that are targeted by immune responses that prevent disease due to malaria and will identify the leading candidate antigens that the Department of Defense and other agencies can subsequently test in preclinical and clinical evaluations. A vaccine that prevented specific forms of malarial disease in soldiers who did become infected would prevent the major casualty threat to US troops operating in the tropics.