Assessing the role of liver stage antigens-specific antibodies against Plasmodium falciparum liver stage infection

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PROJECT SUMMARY The recent discovery of Plasmodium falciparum (Pf) liver stage antigens (LS Ags) is providing us with an opportunity for conducting explorations of the utility of these Ags as vehicles to prevent malaria and also as tools for seeking a better understanding of the Plasmodium LS development. Amongst the Plasmodium spp., Pf remains one of the deadliest infectious diseases that plagues many parts of the world and anti-malaria approaches are not fully effective. Currently, these approaches have been shifting towards the development of human monoclonal antibodies (hmAbs) as a more effective anti-malaria measure. Clinical trials are underway with hmAbs directed to a single target, the circumsporozoite protein (CSP). It is likely that similar to CSP- based RTS,S vaccine, mAbs directed to a single Ag, the CSP, may be insufficient to prevent malaria. Even a single spz that escapes anti-CSP Abs will infect hepatocytes and initiate clinical malaria. We are proposing an alternative strategy that may improve the CSP-based preventative measures. We would incorporate Ags expressed during the Plasmodium LS development. We hypothesize that a combination of Ags that includes CSP and LS Ags would provide a broader Ab specificities and a wider coverage against the parasite. We have previously demonstrated in a mouse model that P. berghei and P. yoelii LS Ags, orthologues of Pf LS Ags, reduce liver parasite burden (LPB) following spz challenge. When co-administered with Pb CSP, some Pb LS Ags induced sterile protection in 80% as compared with ~40% protection of mice that received only Pb CSP or a combination of the 3 Pb LS Ags. Like CSP, the Pb LS Ags induced antibody responses to Ags on spz and infected hepatocytes. On the basis of these results we hypothesize that a cocktail of mAbs specific for targets on CSP and LS Ags is needed for an efficacious approach to prevent malaria. The availability of the humanized DRAGA mouse - with its developed functional human immune system, human hepatocytes, Kupffer cells, and erythrocytes, which allow complete vertebrate Pf life cycle - presents an ideal model for (1) producing Pf LS Ags-specific hmAbs and (2) subsequently for testing the efficacy of a cocktail of Pf CSP- and LS Ag-specific hmAbs in preventing malaria infection after Pf spz challenge. The successful production Pf LS Ags-specific hmAbs could be used to enhance protection mediated by CSP; these hmAbs also would provide reagents needed towards explorations of the mechanism of liver pathogenicity as well as organ-specific immunogenicity of Plasmodium LS Ags.