title: Multiple clinical episodes of Plasmodium falciparum malaria in a low transmission intensity setting: exposure versus immunity.
abstract: BACKGROUND
  Epidemiological studies indicate that some children experience many more episodes of clinical malaria than their age mates in a given location. Whether this is as a result of the micro-heterogeneity of malaria transmission with some children effectively getting more exposure to infectious mosquitoes than others, or reflects a failure in the acquisition of immunity needs to be elucidated. Here, we investigated the determinants of increased susceptibility to clinical malaria by comparing the intensity of exposure to Plasmodium falciparum and the acquisition of immunity in children at the extreme ends of the over-dispersed distribution of the incidence of clinical malaria.
  
  
  METHODS
  The study was nested within a larger cohort in an area where the intensity of malaria transmission was low. We identified children who over a five-year period experienced 5 to 16 clinical malaria episodes (children at the tail-end of the over-dispersed distribution, n = 35), remained malaria-free (n = 12) or had a single episode (n = 26). We quantified antibodies against seven Plasmodium falciparum merozoite antigens in plasma obtained at six cross-sectional surveys spanning these five years. We analyzed the antibody responses to identify temporal dynamics that associate with disease susceptibility.
  
  
  RESULTS
  Children experiencing multiple episodes of malaria were more likely to be parasite positive by microscopy at cross-sectional surveys (X (2) test for trend 14.72 P = 0.001) and had a significantly higher malaria exposure index, than those in the malaria-free or single episode groups (Kruskal-Wallis test P = 0.009). In contrast, the five-year temporal dynamics of anti-merozoite antibodies were similar in the three groups. Importantly in all groups, antibody levels were below the threshold concentrations previously observed to be correlated with protective immunity.
  
  
  CONCLUSIONS
  We conclude that in the context of a low malaria transmission setting, susceptibility to clinical malaria is not accounted for by anti-merozoite antibodies but appears to be a consequence of increased parasite exposure. We hypothesize that intensive exposure is a prerequisite for protective antibody concentrations, while little to modest exposure may manifest as multiple clinical infections with low levels of antibodies. These findings have implications for interventions that effectively lower malaria transmission intensity.
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. josea_rono@e-kconsulting.com.|Infectious Diseases Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. josea_rono@e-kconsulting.com.
authors.forename: Josea
authors.initials: J
authors.lastname: Rono
authors.affiliation: Infectious Diseases Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. anna.farnert@ki.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Färnert
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. LMurungi@kemri-wellcome.org.
authors.forename: Linda
authors.initials: L
authors.lastname: Murungi
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. JOjal@kemri-wellcome.org.
authors.forename: John
authors.initials: J
authors.lastname: Ojal
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. GKamuyu@kemri-wellcome.org.
authors.forename: Gathoni
authors.initials: G
authors.lastname: Kamuyu
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. FGuleid@kemri-wellcome.org.
authors.forename: Fatuma
authors.initials: F
authors.lastname: Guleid
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. GNyangweso@kemri-wellcome.org.
authors.forename: George
authors.initials: G
authors.lastname: Nyangweso
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. JWambua@kemri-wellcome.org.
authors.forename: Juliana
authors.initials: J
authors.lastname: Wambua
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. BKitsao@kemri-wellcome.org.
authors.forename: Barnes
authors.initials: B
authors.lastname: Kitsao
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. AOlotu@kemri-wellcome.org.
authors.forename: Ally
authors.initials: A
authors.lastname: Olotu
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. KMarsh@kemri-wellcome.org.|Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, UK. KMarsh@kemri-wellcome.org.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya. FOsier@kemri-wellcome.org.
authors.forename: Faith Ha
authors.initials: FH
authors.lastname: Osier
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000276:immunology* / Q000635:transmission; D008297:Male; D010963:Plasmodium falciparum
chemical_list: D000913:Antibodies, Protozoan