Generation of Plasmodium falciparum parasite-inhibitory antibodies by immunization with recombinantly-expressed CyRPA

Malaria Journal

Research

Gerd Pluschke¹  Anita M. Dreyer¹  Paola Favuzza¹  Guy Riccio¹  Simon Blaser¹  Marco Tamborrini¹  Ralf Thoma²  Hugues Matile² 

[1] Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland;University of Basel, Basel, Switzerland;Roche Pharmaceutical Research & Early Development, Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland;

关键词: Malaria;    CyRPA;    Erythrocyte invasion;    Blood-stage vaccines;   

DOI  :  10.1186/s12936-016-1213-x

 received in 2015-10-28, accepted in 2016-03-05,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe pathogenesis of malaria is primarily associated with blood-stage infection and there is strong evidence that antibodies specific for parasite blood-stage antigens can control parasitaemia. This provides a strong rationale for incorporation of asexual blood-stage antigen components into an effective multivalent malaria subunit vaccine. On the basis of available genome-wide transcriptomic and proteomic data, previously uncharacterized Plasmodium falciparum open reading frames were screened for new blood stage vaccine candidates. This has led to the identification of the cysteine-rich protective antigen (PfCyRPA), which forms together with PfRH5 and PfRipr a multiprotein complex that is crucial for erythrocyte invasion.MethodsGlycosylated and non-glycosylated variants of recombinant PfCyRPA were expressed and produced as secreted protein in mammalian cells. Adjuvanted formulations of purified PfCyRPA were tested to assess whether they can effectively elicit parasite inhibitory antibodies, and to investigate whether or not the glycosylation status affects antibody binding. For this purpose, two sets of PfCyRPA-specific mouse monoclonal antibodies (mAbs) have been raised and evaluated for functional activity.ResultsGenerated PfCyRPA-specific mAbs, irrespective of the immunogen’s glycosylation status, showed substantial parasite in vitro growth-inhibitory activity due to inhibition of erythrocyte invasion by merozoites. Furthermore, passive immunization experiments in P. falciparum infected NOD-scid IL2Rγnull mice engrafted with human erythrocytes demonstrated potent in vivo growth-inhibitory activity of generated mAbs.ConclusionsRecombinantly expressed PfCyRPA tested as adjuvanted vaccine formulations in mice elicited antibodies that significantly inhibit P. falciparum asexual blood stage parasite growth both in vitro and in vivo. These findings render PfCyRPA a promising blood-stage candidate antigen for inclusion into a multicomponent malaria subunit vaccine.

【 授权许可】

CC BY   
© Favuzza et al. 2016