We will generate human monoclonal antibodies that target Plasmodium falciparum antigens that have been implicated in acquired protective immunity to this parasite, which is the causative agent of the most serious form of malaria in humans.
The main antigenic targets of the protective immunity to P. falciparum malaria as it is developed by people living in areas of stable parasite transmission are expressed on the intact surface of infected erythrocytes or free merozoite stage parasites, and are encoded either by polymorphic single-copy genes or by clonally variant multi-gene families. This has greatly frustrated traditional approaches towards the development of effective vaccines as new prophylactic interventions against malaria.
We will employ a new technology, which was developed by one of us and which allows efficient generation and production of human monoclonal antibodies, to generate tools of unprecedented efficacy in malaria vaccine research. In addition, such human monoclonal antibodies with specificity for targets of protective immunity against malaria hold the promise of new intervention in the form of passive therapeutic immunization. The ambition is to provide 'proof-of-principle' data by developing human monoclonal antibodies with specificity for a representative polymorphic single-copy antigen (PfMSP1) and for specific members of the PfEMP1 antigens encoded by the clonally variant var multi-gene family. Both PfMSP1 and PfEMP1 are strongly implicated in protective immunity to P. falciparum malaria, not least because of research by the applicants. The project goes clearly beyond the current state-of-the-art in malaria research by combining groundbreaking technology with rational, evidence-based selection of candidate parasite antigens as targets of therapeutic and prophylactic intervention. The approach taken holds the promise of overcoming existing obstacles to efficient intervention against malaria.
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