title: Strain-specific Plasmodium falciparum multifunctional CD4(+) T cell cytokine expression in Malian children immunized with the FMP2.1/AS02A vaccine candidate.
abstract: Based on Plasmodium falciparum (Pf) apical membrane antigen 1 (AMA1) from strain 3D7, the malaria vaccine candidate FMP2.1/AS02A showed strain-specific efficacy in a Phase 2 clinical trial in 400 Malian children randomized to 3 doses of the AMA1 vaccine candidate or control rabies vaccine on days 0, 30 and 60. A subset of 10 Pf(-) (i.e., no clinical malaria episodes) AMA1 recipients, 11 Pf(+) (clinical malaria episodes with parasites with 3D7 or Fab9-type AMA1 cluster 1 loop [c1L]) AMA1 recipients, and 10 controls were randomly chosen for analysis. Peripheral blood mononuclear cells (PBMCs) isolated on days 0, 90 and 150 were stimulated with full-length 3D7 AMA1 and c1L from strains 3D7 (c3D7) and Fab9 (cFab9). Production of IFN-γ, TNF-α, IL-2, and/or IL-17A was analyzed by flow cytometry. Among AMA1 recipients, 18/21 evaluable samples stimulated with AMA1 demonstrated increased IFN-γ, TNF-α, and IL-2 derived from CD4(+) T cells by day 150 compared to 0/10 in the control group (p<0.0001). Among AMA1 vaccines, CD4(+) cells expressing both TNF-α and IL-2 were increased in Pf(-) children compared to Pf(+) children. When PBMCs were stimulated with c3D7 and cFab9 separately, 4/18 AMA1 recipients with an AMA1-specific CD4(+) response had a significant response to one or both c1L. This suggests that recognition of the AMA1 antigen is not dependent upon c1L alone. In summary, AMA1-specific T cell responses were notably increased in children immunized with an AMA1-based vaccine candidate. The role of CD4(+)TNF-α(+)IL-2(+)-expressing T cells in vaccine-induced strain-specific protection against clinical malaria requires further exploration. Clinicaltrials.gov Identifier: NCT00460525.
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, United States.
authors.forename: Shawna F
authors.initials: SF
authors.lastname: Graves
authors.affiliation: Malaria Research and Training Center, University of Science, Techniques and Technology, Bamako, Mali.
authors.forename: Bourema
authors.initials: B
authors.lastname: Kouriba
authors.affiliation: Malaria Research and Training Center, University of Science, Techniques and Technology, Bamako, Mali.
authors.forename: Issa
authors.initials: I
authors.lastname: Diarra
authors.affiliation: Malaria Research and Training Center, University of Science, Techniques and Technology, Bamako, Mali.
authors.forename: Modibo
authors.initials: M
authors.lastname: Daou
authors.affiliation: Malaria Research and Training Center, University of Science, Techniques and Technology, Bamako, Mali.
authors.forename: Amadou
authors.initials: A
authors.lastname: Niangaly
authors.affiliation: Malaria Research and Training Center, University of Science, Techniques and Technology, Bamako, Mali.
authors.forename: Drissa
authors.initials: D
authors.lastname: Coulibaly
authors.affiliation: Malaria Research and Training Center, University of Science, Techniques and Technology, Bamako, Mali.
authors.forename: Yamoussa
authors.initials: Y
authors.lastname: Keita
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, United States; Howard Hughes Medical Institute, University of Maryland, Baltimore, MD, United States.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Laurens
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, United States; Howard Hughes Medical Institute, University of Maryland, Baltimore, MD, United States.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Berry
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: W
authors.initials: W
authors.lastname: Ripley Ballou
authors.affiliation: Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Lanar
authors.affiliation: Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
authors.forename: D
authors.initials: D
authors.lastname: Gray Heppner
authors.affiliation: Malaria Vaccine Development Program, U.S. Agency for International Development, Washington, DC, United States.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Soisson
authors.affiliation: Malaria Vaccine Development Program, U.S. Agency for International Development, Washington, DC, United States.
authors.forename: Carter L
authors.initials: CL
authors.lastname: Diggs
authors.affiliation: Malaria Research and Training Center, University of Science, Techniques and Technology, Bamako, Mali.
authors.forename: Mahamadou A
authors.initials: MA
authors.lastname: Thera
authors.affiliation: Malaria Research and Training Center, University of Science, Techniques and Technology, Bamako, Mali.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, United States; Howard Hughes Medical Institute, University of Maryland, Baltimore, MD, United States.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, United States.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, United States. Electronic address: klyke@medicine.umaryland.edu.
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Lyke
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary; D007223:Infant; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D017780:Malaria Vaccines / Q000627:therapeutic use*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008302:Mali; D008565:Membrane Proteins / Q000276:immunology*; D010963:Plasmodium falciparum; D015800:Protozoan Proteins / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D016207:Cytokines; C573415:IFNG protein, human; C508717:IL17A protein, human; C508594:IL2 protein, human; D020381:Interleukin-17; D007376:Interleukin-2; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D014409:Tumor Necrosis Factor-alpha; C090077:apical membrane antigen I, Plasmodium; D007371:Interferon-gamma
keywords: AMA1; FMP2.1/AS02(A); Malaria; Multifunctional; Pediatric; T cell