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.
Subject(s)
Antigens, Protozoan/immunology , CD4-Positive T-Lymphocytes/immunology , Cytokines/immunology , Malaria Vaccines/therapeutic use , Malaria, Falciparum/prevention & control , Membrane Proteins/immunology , Protozoan Proteins/immunology , Adjuvants, Immunologic/administration & dosage , Antibodies, Protozoan/blood , Child , Child, Preschool , Humans , Immunization, Secondary , Infant , Interferon-gamma/immunology , Interleukin-17/immunology , Interleukin-2/immunology , Mali , Plasmodium falciparum , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Attenuated pre-erythrocytic stage malaria vaccines protect humans from sporozoite challenge. Current technology limits the feasibility of their commercial scale production and poses a significant risk of contamination with transmissible agents. Overcoming these barriers will be very challenging. In contrast, subunit vaccines appear quite feasible and show great promise as candidate malaria vaccines.
