We have ongoing human and nonhuman primate studies to investigate malaria immunology and pathogenesis during pregnancy, and severe malaria pathogenesis. Highlighted in this years summary are results from our publications. Developing a novel risk prediction model for severe malarial anemia. As a pilot study to investigate whether personalized medicine approaches could have value for the reduction of malaria-related mortality in young children, we evaluated questionnaire and biomarker data collected from the Mother Offspring Malaria Study Project birth cohort (Muheza, Tanzania, 20022006) at the time of delivery as potential prognostic markers for pediatric severe malarial anemia. Severe malarial anemia, defined here as a Plasmodium falciparum infection accompanied by hemoglobin levels below 50 g/L, is a key manifestation of life-threatening malaria in high transmission regions. For this study sample, a prediction model incorporating cord blood levels of interleukin-1 provided the strongest discrimination of severe malarial anemia risk with a C-index of 0.77 (95% CI 0.700.84), whereas a pragmatic model based on sex, gravidity, transmission season at delivery, and bed net possession yielded a more modest C-index of 0.63 (95% CI 0.540.71). Although additional studies, ideally incorporating larger sample sizes and higher event per predictor ratios, are needed to externally validate these prediction models, the findings provide proof of concept that risk score-based screening programs could be developed to avert severe malaria cases in early childhood. Identification of protective B-cell epitopes within the novel malaria vaccine candidate P. falciparum Schizont Egress Antigen-1. Naturally acquired antibodies to Plasmodium falciparum schizont egress antigen 1 (PfSEA-1A) are associated with protection against severe malaria in children. Vaccination of mice with SEA-1A from Plasmodium berghei (PbSEA-1A) decreases parasitemia and prolongs survival following P. berghei ANKA challenge. To enhance the immunogenicity of PfSEA-1A, we identified five linear B-cell epitopes using peptide microarrays probed with antisera from nonhuman primates vaccinated with recombinant PfSEA-1A (rPfSEA-1A). We evaluated the relationship between epitope-specific antibody levels and protection from parasitemia in a longitudinal treatment-reinfection cohort in western Kenya. Antibodies to three epitopes were associated with 16 to 17% decreased parasitemia over an 18-week high transmission season. We are currently designing immunogens to enhance antibody responses to these three epitopes. Maternal microchimerism predicts increased infection but decreased disease due to P. falciparum during early childhood. A mother's infection with placental malaria (PM) can affect her child's susceptibility to malaria, although the mechanism remains unclear. The fetus acquires a small amount of maternal cells and DNA known as maternal microchimerism (MMc), and we hypothesized that PM increases MMc and that MMc alters risk of Plasmodium falciparum malaria during infancy. In a nested cohort from Muheza, Tanzania, we evaluated the presence and level of cord blood MMc in offspring of women with and without PM. A maternal-specific polymorphism was identified for each maternal-infant pair, and MMc was assayed by quantitative polymerase chain reaction. The ability of MMc to predict malaria outcomes during early childhood was evaluated in longitudinal models. Inflammatory PM increased the detection rate of MMc among offspring of primigravidae and secundigravidae, and both noninflammatory and inflammatory PM increased the level of MMc. Detectable MMc predicted increased risk of positive blood smear but, interestingly, decreased risk of symptomatic malaria and malaria hospitalization. The acquisition of MMc may result in increased malaria infection but protection from malaria disease. Future studies should be directed at the cellular component of MMc, with attention to its ability to directly or indirectly coordinate anti-malarial immune responses in the offspring. A malaria-resistant phenotype with immunological correlates in a Tanzanian birth cohort exposed to intense malaria transmission. Malaria incidence is highly heterogeneous even in areas of high transmission, although no conclusive evidence exists that innate or naturally acquired resistance can prevent infection over an extended period of time. This longitudinal study examined immunoparasitological evidence for a malaria-resistant phenotype in which children do not develop malaria despite an extended period of exposure to parasites. Within a birth cohort followed from 2002 to 2006 in Muheza, Tanzania, an area of intense transmission, children (N = 687) provided blood smears biweekly during infancy and monthly thereafter. Maternal and childhood characteristics were obtained, cord-blood cytokines were measured, and antibody responses were assayed as measures of stage-specific exposure. Sixty-three (9.2%) children had no blood smear-positive slides over 2 years of follow-up (range: 1-3.5 years) and were identified as malaria resistant. Malaria-resistant children were similar to other children with respect to completeness of follow-up and all maternal and childhood characteristics except residence area. Antibody seroprevalence was similar for two sporozoite antigens, but malaria-resistant children had a lower antibody seroprevalence to merozoite antigens merozoite surface protein 1 (5.4% versus 30.2%; P < 0.0001) and apical membrane antigen 1 (7.2% versus 33.3%; P < 0.0001). Malaria-resistant children had higher cytokine levels in cord blood, particularly interleukin-1. In summary, a subset of children living in an area of intense transmission was exposed to malaria parasites, but never developed patent parasitemia; this phenotype was associated with a distinct cytokine profile at birth and antibody profile during infancy. Further research with malaria-resistant children may identify mechanisms for naturally acquired immunity.
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