title: Effective Antimalarial Chemoprevention in Childhood Enhances the Quality of CD4+ T Cells and Limits Their Production of Immunoregulatory Interleukin 10.
abstract: Experimental inoculation of viable Plasmodium falciparum sporozoites administered with chemoprevention targeting blood-stage parasites results in protective immunity. It is unclear whether chemoprevention similarly enhances immunity following natural exposure to malaria.
  
  
  
  We assessed P. falciparum-specific T-cell responses among Ugandan children who were randomly assigned to receive monthly dihydroartemisinin-piperaquine (DP; n = 87) or no chemoprevention (n = 90) from 6 to 24 months of age, with pharmacologic assessments for adherence, and then clinically followed for an additional year.
  
  
  
  During the intervention, monthly DP reduced malaria episodes by 55% overall (P < .001) and by 97% among children who were highly adherent to DP (P < .001). In the year after the cessation of chemoprevention, children who were highly adherent to DP had a 55% reduction in malaria incidence as compared to children given no chemoprevention (P = .004). Children randomly assigned to receive DP had higher frequencies of blood-stage specific CD4(+) T cells coproducing interleukin-2 and tumor necrosis factor α (P = .003), which were associated with protection from subsequent clinical malaria and parasitemia, and fewer blood-stage specific CD4(+) T cells coproducing interleukin-10 and interferon γ (P = .001), which were associated with increased risk of malaria.
  
  
  
  In this setting, effective antimalarial chemoprevention fostered the development of CD4(+) T cells that coproduced interleukin 2 and tumor necrosis factor α and were associated with prospective protection, while limiting CD4(+) T-cell production of the immunoregulatory cytokine IL-10.
authors.affiliation: Department of Medicine, San Francisco General Hospital.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Jagannathan
authors.affiliation: Department of Medicine, San Francisco General Hospital.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bowen
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Felistas
authors.initials: F
authors.lastname: Nankya
authors.affiliation: Department of Medicine, San Francisco General Hospital.
authors.forename: Tara I
authors.initials: TI
authors.lastname: McIntyre
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Ann
authors.initials: A
authors.lastname: Auma
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Samuel
authors.initials: S
authors.lastname: Wamala
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Esther
authors.initials: E
authors.lastname: Sikyomu
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Kate
authors.initials: K
authors.lastname: Naluwu
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Mayimuna
authors.initials: M
authors.lastname: Nalubega
authors.affiliation: Department of Medicine, San Francisco General Hospital Center for Biomedical Research, The Burnet Institute, Melbourne, Australia.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Boyle
authors.affiliation: Department of Medicine, San Francisco General Hospital.
authors.forename: Lila A
authors.initials: LA
authors.lastname: Farrington
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Victor
authors.initials: V
authors.lastname: Bigira
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: James
authors.initials: J
authors.lastname: Kapisi
authors.affiliation: Department of Clinical Pharmacy.
authors.forename: Fran
authors.initials: F
authors.lastname: Aweeka
authors.affiliation: Department of Medicine, San Francisco General Hospital.
authors.forename: Bryan
authors.initials: B
authors.lastname: Greenhouse
authors.affiliation: Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Moses
authors.initials: M
authors.lastname: Kamya
authors.affiliation: Department of Medicine, San Francisco General Hospital.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department of Medicine, San Francisco General Hospital Department of Pediatrics, University of California-San Francisco.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Feeney
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018890:Chemoprevention / Q000379:methods*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D016753:Interleukin-10 / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D011804:Quinolines / Q000008:administration & dosage; D014454:Uganda; D055815:Young Adult; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D016753:Interleukin-10; D011804:Quinolines; C508609:IL10 protein, human; C039060:artenimol; C034759:piperaquine; D010879:Piperazines
keywords: IL-10; IL-2; T cell; antimalarial chemoprevention; falciparum; immunity; malaria