title: A recombinant Bacille Calmette-Guérin construct expressing the Plasmodium falciparum circumsporozoite protein enhances dendritic cell activation and primes for circumsporozoite-specific memory cells in BALB/c mice.
abstract: A protective malaria vaccine may induce both high levels of neutralising antibodies and strong T-cell responses. The Plasmodium falciparum circumsporozoite protein (CSp) is a leading pre-erythrocytic vaccine candidate. CSp is a week immunogen per se, but Mycobacterium bovis Bacille Calmette-Guérin (BCG) has excellent adjuvant activity and has been utilized as a vector to deliver heterologous vaccine candidate antigens. It is safe in immunocompetent individuals and inexpensive to produce. We assessed in vitro and in vivo a recombinant BCG-expressing CSp (BCG-CS) as malaria vaccine candidate. Immunisation of BALB/c mice with BCG-CS augmented numbers of dendritic cells (DCs) in draining lymph nodes and in the spleen. The activation markers MHC-class-II, CD40, CD80 and CD86 on DCs were significantly upregulated by BCG-CS as compared to wild-type BCG (wt-BCG). In vitro stimulation of bone marrow-derived DCs and macrophages with BCG-CS induced IL-12 and TNF-α production. BCG-CS induced higher phagocytic activity in macrophages as compared to wt-BCG. Immunogenicity studies show that BCG-CS induced CS-specific antibodies and IFN-γ-producing memory cells. In conclusion, BCG-CS is highly efficient in activating antigen-presenting cells (APCs) for priming of adaptive immunity. Implications for the rational design of novel vaccines against malaria and TB, the two major devastating poverty-related diseases, are discussed.
authors: Department of Immunology, Wenner-Gren Institute, Stockholm University, Sweden.
authors: Charles
authors: C
authors: Arama
authors: Shahid
authors: S
authors: Waseem
authors: Carmen
authors: C
authors: Fernández
authors: Yohannes
authors: Y
authors: Assefaw-Redda
authors: Liya
authors: L
authors: You
authors: Ariane
authors: A
authors: Rodriguez
authors: Katarina
authors: K
authors: Radošević
authors: Jaap
authors: J
authors: Goudsmit
authors: Stefan H E
authors: SH
authors: Kaufmann
authors: Stephen T
authors: ST
authors: Reece
authors: Marita
authors: M
authors: Troye-Blomberg
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009163:Mycobacterium bovis / Q000235:genetics*; D010587:Phagocytosis / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015415:Biomarkers; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014409:Tumor Necrosis Factor-alpha; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan; D018664:Interleukin-12; D007371:Interferon-gamma