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Tricomponent complex loaded with a mosquito-stage antigen of the malaria parasite induces potent transmission-blocking immunity.

ABSTRACT: The development of malaria vaccines is challenging, partly because the immunogenicity of recombinant malaria parasite antigens is low. We previously demonstrated that parasite antigens integrated into a tricomponent immunopotentiating complex increase antiparasitic immunity. In this study, the B domains of a group G Streptococcus (SpG) strain and Peptostreptococcus magnus (PpL) were used to evaluate whether vaccine efficacy is influenced by the type of immunoglobulin-binding domain (IBD) in the tricomponent complex. IBDs were fused to a pentameric cartilage oligomeric matrix protein (COMP) to increase the binding avidity of the complexes for their targets. The COMP-IBD fusion proteins generated (COMP-SpG and COMP-PpL and the previously constructed COMP-Z) bound a large fraction of splenic B lymphocytes but not T lymphocytes. These carrier molecules were then loaded with an ookinete surface protein of Plasmodium vivax, Pvs25, by chemical conjugation. The administration of the tricomponent complexes to mice induced more Pvs25-specific serum IgG than did the unloaded antigen. The PpL complex, which exhibited a broad Ig-binding spectrum, conferred higher vaccine efficacy than did the Z or SpG complexes when evaluated with a membrane feed assay. This study demonstrates that this tricomponent immunopotentiating system, incorporating IBDs as the B-lymphocyte-targeting ligands, is a promising technology for the delivery of malaria vaccines, particularly when combined with an aluminum salt adjuvant.

SUBMITTER: Arakawa T

PROVIDER: S-EPMC3993126 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Tricomponent complex loaded with a mosquito-stage antigen of the malaria parasite induces potent transmission-blocking immunity.

Arakawa Takeshi T Tsuboi Takafumi T Sattabongkot Jetsumon J Sakao Kozue K Torii Motomi M Miyata Takeshi T

Clinical and vaccine immunology : CVI 20140212 4

The development of malaria vaccines is challenging, partly because the immunogenicity of recombinant malaria parasite antigens is low. We previously demonstrated that parasite antigens integrated into a tricomponent immunopotentiating complex increase antiparasitic immunity. In this study, the B domains of a group G Streptococcus (SpG) strain and Peptostreptococcus magnus (PpL) were used to evaluate whether vaccine efficacy is influenced by the type of immunoglobulin-binding domain (IBD) in the ...[more]

PMID: 24521783

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Project description:Background:Despite recent successes at controlling malaria, progress has stalled with an estimated 219 million cases and 435,000 deaths in 2017 alone. Combined with emerging resistance to front line antimalarial therapies in Southeast Asia, there is an urgent need for new treatment options and novel approaches to halt the spread of malaria. Plasmodium, the parasite responsible for malaria propagates through mosquito transmission. This imposes an acute bottleneck on the parasite population and transmission-blocking interventions exploiting this vulnerability are recognized as vital for malaria elimination. Methods:13,533 small molecules with known activity against Plasmodium falciparum asexual parasites were screened for additional transmission-blocking activity in an ex vivo Plasmodium berghei ookinete development assay. Active molecules were then counterscreened in dose response against HepG2 cells to determine their activity/cytotoxicity window and selected non-toxic representative molecules were fully profiled in a range of transmission and mosquito infection assays. Furthermore, the entire dataset was compared to other published screens of the same molecules against P. falciparum gametocytes and female gametogenesis. Results:437 molecules inhibited P. berghei ookinete formation with an IC50 < 10 ?M. of which 273 showed >10-fold parasite selectivity compared to activity against HepG2 cells. Active molecules grouped into 49 chemical clusters of three or more molecules, with 25 doublets and 94 singletons. Six molecules representing six major chemical scaffolds confirmed their transmission-blocking activity against P. falciparum male and female gametocytes and inhibited P. berghei oocyst formation in the standard membrane feeding assay at 1 ?M. When screening data in the P. berghei development ookinete assay was compared to published screens of the same library in assays against P. falciparum gametocytes and female gametogenesis, it was established that each assay identified distinct, but partially overlapping subsets of transmission-blocking molecules. However, selected molecules unique to each assay show transmission-blocking activity in mosquito transmission assays. Conclusion:The P. berghei ookinete development assay is an excellent high throughput assay for efficiently identifying antimalarial molecules targeting early mosquito stage parasite development. Currently no high throughput transmission-blocking assay is capable of identifying all transmission-blocking molecules.

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Tricomponent complex loaded with a mosquito-stage antigen of the malaria parasite induces potent transmission-blocking immunity.

Publications

Tricomponent complex loaded with a mosquito-stage antigen of the malaria parasite induces potent transmission-blocking immunity.

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