Recombinant Mycobacterium bovis Bacillus Calmette-Guérin Secreting Merozoite Surface Protein 1 (MSP1) Induces Protection against Rodent Malaria Parasite Infection Depending on MSP1-stimulated Interferon γ and Parasite-specific Antibodies

Abstract

The merozoite surface protein 1 (MSP1) has emerged as a leading malaria vaccine candidate at the erythrocytic stage. Recombinant bacillus Calmette-Guérin (rBCG), which expressed a COOH-terminal 15-kD fragment of MSP1 of Plasmodium yoelii (MSP1-15) as a fusion protein with a secretory protein of Mycobacterium kansasii, was constructed. Immunization of mice with this rBCG induced a higher degree of protection against blood-stage parasite infection than with recombinant MSP1-15 in the RIBI adjuvant (RIBI ImmunoChem Research, Inc., Hamilton, MT) or incomplete Freund's adjuvant systems. We studied the mechanism of protection induced by MSP1-15, and found that interferon (IFN)-γ had a major role in protection in all adjuvant systems we examined. Mice that produced low amounts of MSP1-15 stimulated IFN-γ and could not control parasite infection. The antibody against MSP1-15 did not play a major role in protection in this system. After parasite infection, immunoglobulin G2a antibodies, which had been produced by IFN-γ stimulation, were induced and subsequently played an important role in eradicating parasites. Thus, both cellular and humoral immune responses were essential for protection from malaria disease. These data revealed that BCG is a powerful adjuvant to induce such a protective immune response against malaria parasites.

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

“…Finally, we analyzed immune responses in PyL-infected TLR9 Ϫ/Ϫ mice. CD4 ϩ T cells and their product IFN-␥ are known to be important for protection against blood-stage malaria (34,35). Flow cytometric analyses revealed that infection of TLR9 Ϫ/Ϫ mice with PyL increased activated (CD62L low , CD69 high ) and IFN-␥ ϩ populations among splenic CD4 ϩ T cells, compared with infection of WT mice (Fig.…”

Immunomodulatory effects of recombinant BCG expressing MSP-1C ofPlasmodium falciparumon LPS- or LPS+IFN-γ-stimulated J774A.1 cells

“…34 This protein is responsible for protective immunity against malaria infection, 35,36 and is one of the most promising malaria vaccine candidates. 29,37,38 We have previously described antibodies produced against the rBCG vaccine inhibited P. falciparum 3D7 merozoite invasion of red blood cells in vitro. 33 Moreover, the rBCG strain also stimulated higher cellular and humoral immune responses in animal model.…”

“…Mycobacterium bovis bacille Calmette-Guérin (BCG), the only vaccine currently available for the prevention of tuberculosis, is among the most extensively used vector for developing recombinant vaccines for other diseases, including malaria. [29][30][31] Using this strategy, our group previously cloned and expressed a synthetic gene encoding the C-terminus of the merozoite surface protein-1 (MSP-1 19 ; referred in this study as MSP-1C) in a recombinant BCG (rBCG016; referred in this study as rBCG) construct. 32,33 MSP-1C is a 19 kDa blood-stage antigen produced by proteolysis of a high molecular weight precursor, 195 kDa MSP-1 protein.…”

Escherichia coliExpressing Recombinant Antigen and Listeriolysin O Stimulate Class I-Restricted CD8+ T Cells following Uptake by Human APC

“…Although immune responses against recombinant Ags were often generated in the mouse system, this does not always translate to humans. For example, vaccination with rBCG as Ag carrier produced Ag-specific Th1 response and protective serum Ab against Plasmodium yoelii in rodents (41). In a clinical trial involving human subjects, the intradermal administration of rBCG vector failed to stimulate Ab responses against delivered Ag (42).…”