title: Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study.
abstract: BACKGROUND
  We have shown that immunity to infection with Plasmodium falciparum can be induced experimentally in malaria-naive volunteers through immunisation by bites of infected mosquitoes while simultaneously preventing disease with chloroquine prophylaxis. This immunity was associated with parasite-specific production of interferon γ and interleukin 2 by pluripotent effector memory cells in vitro. We aim to explore the persistence of protection and immune responses in the same volunteers.
  
  
  METHODS
  In an open-label study at the Radboud University Nijmegen Medical Centre (Nijmegen, Netherlands), from November to December, 2009, we rechallenged previously immune volunteers (28 months after immunisation) with the bites of five mosquitoes infected with P falciparum. Newly recruited malaria-naive volunteers served as infection controls. Our primary outcome was the detection of blood-stage parasitaemia by microscopy. We assessed the kinetics of parasitaemia with real-time quantitative PCR (rtPCR) and recorded clinical signs and symptoms. In-vitro production of interferon γ and interleukin 2 by effector memory T cells was studied after stimulation with sporozoites and red blood cells infected with P falciparum. Differences in cellular immune responses between the study groups were assessed with the Mann-Whitney test. This study is registered with ClinicalTrials.gov, number NCT00757887.
  
  
  RESULTS
  Four of six immune volunteers were microscopically negative after rechallenge. rtPCR-based detection of blood-stage parasites in these individuals was negative throughout follow-up. Patent parasitaemia was delayed in the remaining two immunised volunteers. In-vitro assays showed the long-term persistence of parasite-specific pluripotent effector memory T-cell responses in protected volunteers. The four protected volunteers reported several mild to moderate adverse events, of which the most commonly reported symptom was headache (one to three episodes per volunteer). The two patients with delayed patency had adverse events similar to those in the control group.
  
  
  CONCLUSIONS
  Artificially induced immunity lasts longer than generally recorded after natural exposure; providing a new avenue of research into the mechanisms of malaria immunity.
  
  
  BACKGROUND
  Dioraphte Foundation.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Meta
authors.initials: M
authors.lastname: Roestenberg
authors.forename: Anne C
authors.initials: AC
authors.lastname: Teirlinck
authors.forename: Matthew B B
authors.initials: MB
authors.lastname: McCall
authors.forename: Karina
authors.initials: K
authors.lastname: Teelen
authors.forename: Krystelle Nganou
authors.initials: KN
authors.lastname: Makamdop
authors.forename: Jorien
authors.initials: J
authors.lastname: Wiersma
authors.forename: Theo
authors.initials: T
authors.lastname: Arens
authors.forename: Pieter
authors.initials: P
authors.lastname: Beckers
authors.forename: GeertJan
authors.initials: G
authors.lastname: van Gemert
authors.forename: Marga
authors.initials: M
authors.lastname: van de Vegte-Bolmer
authors.forename: André J A M
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Adrian J F
authors.initials: AJ
authors.lastname: Luty
authors.forename: Cornelus C
authors.initials: CC
authors.lastname: Hermsen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000328:Adult; D000918:Antibody Specificity / Q000276:immunology; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D002738:Chloroquine / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007114:Immunization / Q000009:adverse effects / Q000379:methods*; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control*; D008297:Male; D009426:Netherlands; D010963:Plasmodium falciparum / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034101:Sporozoites / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: D000962:Antimalarials; D007376:Interleukin-2; D007371:Interferon-gamma; D002738:Chloroquine