title: Cytotoxic markers associate with protection against malaria in human volunteers immunized with Plasmodium falciparum sporozoites.
abstract: BACKGROUND
  Immunization of healthy volunteers by bites from Plasmodium falciparum-infected mosquitoes during chloroquine chemoprophylaxis (hereafter, chemoprophylaxis and sporozoites [CPS] immunization) induces sterile protection against malaria. CPS-induced protection is mediated by immunity against pre-erythrocytic stages, presumably at least partially by cytotoxic cellular responses. We therefore aimed to investigate the association of CPS-induced cytotoxic T-cell markers with protection.
  
  
  METHODS
  In a double-blind randomized controlled trial, we performed dose titration of CPS immunization followed by homologous challenge infection in 29 subjects. Immune responses were assessed by in vitro restimulation of peripheral blood mononuclear cells and flow cytometry.
  
  
  RESULTS
  Dose-dependent complete protection was obtained in 4 of 5 volunteers after immunization with bites from 45 P. falciparum-infected mosquitoes, in 8 of 9 volunteers with bites from 30, and in 5 of 10 volunteers with bites from 15 (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.5-17). Completely protected subjects had significantly higher proportions of CD4 T cells expressing the degranulation marker CD107a (OR, 8.4; 95% CI, 1.5-123; P = .011) and CD8 cells producing granzyme B (OR, 11; 95% CI, 1.9-212; P = .004) after P. falciparum restimulation.
  
  
  CONCLUSIONS
  These data underline the efficiency of CPS immunization to induce sterile protection and support a possible role for cytotoxic CD4 and CD8 T-cell responses in pre-erythrocytic immunity.
  
  
  BACKGROUND
  NCT01218893.
authors.affiliation: Department of Medical Microbiology.
authors.forename: Else M
authors.initials: EM
authors.lastname: Bijker
authors.affiliation: Department of Medical Microbiology.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Teirlinck
authors.affiliation: Department of Infectious Diseases.
authors.forename: Remko
authors.initials: R
authors.lastname: Schats
authors.affiliation: Department of Medical Microbiology.
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.affiliation: Department of Medical Microbiology.
authors.forename: Marga
authors.initials: M
authors.lastname: van de Vegte-Bolmer
authors.affiliation: Department of Medical Microbiology, Department of Parasitology, Leiden University Medical Center, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: van Lieshout
authors.affiliation: Department for Health Evidence, Section Biostatistics, Radboud university medical center, Nijmegen.
authors.forename: Joanna
authors.initials: J
authors.lastname: IntHout
authors.affiliation: Department of Medical Microbiology.
authors.forename: Cornelus C
authors.initials: CC
authors.lastname: Hermsen
authors.affiliation: Department of Medical Microbiology.
authors.forename: Anja
authors.initials: A
authors.lastname: Scholzen
authors.affiliation: Department of Infectious Diseases.
authors.forename: Leo G
authors.initials: LG
authors.lastname: Visser
authors.affiliation: Department of Medical Microbiology.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D064368:Healthy Volunteers; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control*; D008297:Male; D010963:Plasmodium falciparum / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D017780:Malaria Vaccines
keywords: Plasmodium; T cells; chloroquine; cytotoxicity; degranulation; granzyme B; immunity; immunization; malaria; protection