title: Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity.
abstract: Volunteers immunized under chloroquine chemoprophylaxis with Plasmodium falciparum sporozoites (CPS) develop complete, long-lasting protection against homologous sporozoite challenge. Chloroquine affects neither sporozoites nor liver-stages, but kills only asexual forms in erythrocytes once released from the liver into the circulation. Consequently, CPS immunization exposes the host to antigens from both preerythrocytic and blood stages, and induced immunity might target either of these stages. We therefore explored the life cycle stage specificity of CPS-induced protection. Twenty-five malaria-naïve volunteers were enrolled in a clinical trial, 15 of whom received CPS immunization. Five immunized subjects and five controls received a sporozoite challenge by mosquito bites, whereas nine immunized and five control subjects received an i.v. challenge with P. falciparum-infected erythrocytes. The latter approach completely bypasses preerythrocytic stages, enabling a direct comparison of protection against either life cycle stage. CPS-immunized subjects (13 of 14) developed anticircumsporozoite antibodies, whereas only one volunteer generated minimal titers against typical blood-stage antigens. IgG from CPS-immunized volunteers did not inhibit asexual blood-stage growth in vitro. All CPS-immunized subjects (5 of 5) were protected against sporozoite challenge. In contrast, nine of nine CPS-immunized subjects developed parasitemia after blood-stage challenge, with identical prepatent periods and blood-stage multiplication rates compared with controls. Intravenously challenged CPS-immunized subjects showed earlier fever and increased plasma concentrations of inflammatory markers D-dimer, IFN-γ, and monokine induced by IFN-γ than i.v. challenged controls. The complete lack of protection against blood-stage challenge indicates that CPS-induced protection is mediated by immunity against preerythrocytic stages. However, evidence is presented for immune recognition of P. falciparum-infected erythrocytes, suggesting memory responses unable to generate functional immunity.
authors.affiliation: Departments of Medical Microbiology, Radboud University Nijmegen Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Else M
authors.initials: EM
authors.lastname: Bijker
authors.forename: Guido J H
authors.initials: GJ
authors.lastname: Bastiaens
authors.forename: Anne C
authors.initials: AC
authors.lastname: Teirlinck
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.forename: Wouter
authors.initials: W
authors.lastname: Graumans
authors.forename: Marga
authors.initials: M
authors.lastname: van de Vegte-Bolmer
authors.forename: Rianne
authors.initials: R
authors.lastname: Siebelink-Stoter
authors.forename: Theo
authors.initials: T
authors.lastname: Arens
authors.forename: Karina
authors.initials: K
authors.lastname: Teelen
authors.forename: Wiebke
authors.initials: W
authors.lastname: Nahrendorf
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Remarque
authors.forename: Will
authors.initials: W
authors.lastname: Roeffen
authors.forename: Annemieke
authors.initials: A
authors.lastname: Jansens
authors.forename: Dunja
authors.initials: D
authors.lastname: Zimmerman
authors.forename: Martijn
authors.initials: M
authors.lastname: Vos
authors.forename: Ben C L
authors.initials: BC
authors.lastname: van Schaijk
authors.forename: Jorien
authors.initials: J
authors.lastname: Wiersma
authors.forename: André J A M
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Quirijn
authors.initials: Q
authors.lastname: de Mast
authors.forename: Lisette
authors.initials: L
authors.lastname: van Lieshout
authors.forename: Jaco J
authors.initials: JJ
authors.lastname: Verweij
authors.forename: Cornelus C
authors.initials: CC
authors.lastname: Hermsen
authors.forename: Anja
authors.initials: A
authors.lastname: Scholzen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000852:Anopheles; D000953:Antigens, Protozoan / Q000276:immunology; D000962:Antimalarials / Q000627:therapeutic use; D002738:Chloroquine / Q000627:therapeutic use*; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D007700:Kinetics; D017780:Malaria Vaccines / Q000627:therapeutic use*; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000517:prevention & control*; D010963:Plasmodium falciparum / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000953:Antigens, Protozoan; D000962:Antimalarials; D017780:Malaria Vaccines; D002738:Chloroquine