Protective human immunity as a vaccine discovery tool for falciparum malaria

BACKGROUND: Plasmodium falciparurn malaria remains a leading cause of morbidity and mortality in developing countries, and malaria-associated severe anemia is the major factor driving the high transfusion requirements in pediatric populations living in endemic areas. STUDY DESIGN AND METHODS: In this report, we identify and evaluate the targets of naturally acquired protective antibody responses in a cohort of n = 143 male volunteers residing in a P falciparum holoendemic area of western Kenya. Volunteers were drug-cured of current malaria infection, blood was collected 2 weeks after treatment, and blood smears were collected weekly for 18 weeks. We identified and pooled plasma from the 10 most resistant (RP) and the 7 most susceptible individuals (SP) and utilized these pools in a differential screen of a P falciparum cDNA expression library. We screened 550,000 clones and identified 7 clones that were uniquely recognized by RP but not by SIR Two clones encoded a C-terminal region polypeptide from rhoptery-associated membrane antigen (RAMA-pr), a recently described rhoptry-associated membrane antigen. RESULTS: We measured RAMA-pr antibody levels in plasma obtained 2 weeks after treatment. Individuals with detectable immunoglobulin G(1) anti-RAMA-pr (n = 24) had fewer positive blood films (p < 0.003) and 43 percent lower density of parasitemia (p < 0.02) than individuals with undetectable (n = 115) antibody levels. CONCLUSION: RAMA-pr is a rationally identified vaccine candidate preferentially recognized by antibodies produced by humans with a high level of naturally acquired resistance to P falciparum infection. Our results demonstrate that naturally acquired protective antibody responses are useful tools to identify vaccine candidates for falciparum malaria.