title: Targets and Mechanisms Associated with Protection from Severe Plasmodium falciparum Malaria in Kenyan Children.
abstract: Severe malaria (SM) is a life-threatening complication of infection with Plasmodium falciparum Epidemiological observations have long indicated that immunity against SM is acquired relatively rapidly, but prospective studies to investigate its immunological basis are logistically challenging and have rarely been undertaken. We investigated the merozoite targets and antibody-mediated mechanisms associated with protection against SM in Kenyan children aged 0 to 2 years. We designed a unique prospective matched case-control study of well-characterized SM clinical phenotypes nested within a longitudinal birth cohort of children (n= 5,949) monitored over the first 2 years of life. We quantified immunological parameters in sera collected before the SM event in cases and their individually matched controls to evaluate the prospective odds of developing SM in the first 2 years of life. Anti-AMA1 antibodies were associated with a significant reduction in the odds of developing SM (odds ratio [OR] = 0.37; 95% confidence interval [CI] = 0.15 to 0.90; P= 0.029) after adjustment for responses to all other merozoite antigens tested, while those against MSP-2, MSP-3, Plasmodium falciparum Rh2 [PfRh2], MSP-119, and the infected red blood cell surface antigens were not. The combined ability of total IgG to inhibit parasite growth and mediate the release of reactive oxygen species from neutrophils was associated with a marked reduction in the odds of developing SM (OR = 0.07; 95% CI = 0.006 to 0.82;P= 0.03). Assays of these two functional mechanisms were poorly correlated (Spearman rank correlation coefficient [rs] = 0.12;P= 0.07). Our data provide epidemiological evidence that multiple antibody-dependent mechanisms contribute to protective immunity via distinct targets whose identification could accelerate the development of vaccines to protect against SM.
authors.affiliation: KEMRI Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya LMurungi@kemri-wellcome.org.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Murungi
authors.affiliation: Unit of Infectious Diseases, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Klara
authors.initials: K
authors.lastname: Sondén
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Llewellyn
authors.affiliation: KEMRI Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya.
authors.forename: Josea
authors.initials: J
authors.lastname: Rono
authors.affiliation: KEMRI Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya.
authors.forename: Fatuma
authors.initials: F
authors.lastname: Guleid
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Williams
authors.affiliation: KEMRI Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya.
authors.forename: Edna
authors.initials: E
authors.lastname: Ogada
authors.affiliation: KEMRI Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya.
authors.forename: Amos
authors.initials: A
authors.lastname: Thairu
authors.affiliation: Unit of Infectious Diseases, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Färnert
authors.affiliation: KEMRI Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya.|Nuffield Department of Medicine, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
authors.affiliation: KEMRI Wellcome Trust Research Programme, Centre for Geographical Medicine Research-Coast, Kilifi, Kenya.
authors.forename: Faith H A
authors.initials: FHA
authors.lastname: Osier
mesh_terms: D000375:Aging; D000913:Antibodies, Protozoan / Q000502:physiology*; D000953:Antigens, Protozoan / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D007223:Infant; D007630:Kenya / Q000453:epidemiology; D016778:Malaria, Falciparum / Q000276:immunology*; D052940:Merozoites / Q000276:immunology; D016017:Odds Ratio; D010963:Plasmodium falciparum / Q000502:physiology*; D016897:Respiratory Burst / Q000502:physiology
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D006131:Growth Inhibitors