This application for continuing studies of immunity to P. falciparum (Pf) will test the hypothesis that a stable pool of CD8+ memory T-cells to liver-stage antigens (Ags) develops by adulthood in residents of malaria endemic areas and that these cells evolve from a genetically diverse repertoire of T-cells elicited by exposure to sporozoites (spz) during infancy. Ongoing studies in Papua New Guinea indicate this area is well suited for examination of immunologic memory in malaria because HLA heterogeneity is limited (HLA-A* 1101 frequency = 67 percent and peptides of vaccine candidate Ags have been confirmed to bind to HLA-A* 1101 and drive T-cell cytokine recall responses.
Aims of continuing studies are to 1) determine whether a genetically stable pool of CD8+ memory T-cells to Pf liver-stage epitopes exists in adults. T-cell lines will be derived from HLA-A* 1101 individuals in order to expand peptide-specific CD8+ T-cell clones. Stability of the pattern of Vbeta expression, CDR3 sequences, and cytokine production will be evaluated over a 2-year period, and 2) assess the relationship between spz exposure and evolution of CD8+ memory cells in a prospective cohort study on children from 4-6 months to 3 years of age. Cytokine responses and TCR usage by HLA-A11-restricted LSA1 peptide-specific T-cells will be correlated with the frequency of infection, high-density parasitemia, genotypic complexity of infection, and uncomplicated morbidity. The studies are relevant to the development of malaria vaccines because these immunogens will ultimately be evaluated in persons with active or previous infection and because maintenance of vaccine-induced immunity will depend on boosting through continuing exposure to spz.
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