DISCOVERY OF ANTIBODIES AGAINST THE BLOOD STAGE OF THE MALARIA PARASITE

Malaria remains a significant global health problem that would greatly benefit from the development of avaccine. Protection against clinical disease could be achieved by eliciting a protective immune responseagainst the blood stage of the malaria parasite. However, only a very limited number of vaccine candidates arecurrently being studied. One approach to uncover novel potential vaccine targets is to analyze protective anti-malaria immunity in response to natural infection. Natural Plasmodium falciparum infections induce antibodyresponses that target the blood stage of this parasite. With repeated exposures, these responses accumulateto a level that protects against symptomatic disease. While dissection of the antibody specificities responsiblefor disease protection has taught us much about protective B-cell immunity, a large fraction of potential B-cellantigens has thus far remained unexplored. In this project, I propose to develop an unbiased platform to isolateantibodies that interfere with parasite replication during the malaria blood stage. In specific Aim 1, I will selectindividuals living in malaria-endemic regions who have developed protective immunity against the parasite andscreen their serum for the capacity to bind to merozoites. A subset of individuals with serum reactivity againstdiverse parasite isolates will be selected for further study. In specific Aim 2, memory B cells will be isolatedfrom these subjects and will be individually cultured to produce antibodies. These monoclonal antibodies willbe screened for the ability to bind merozoites and induce opsonic phagocytosis. In specific Aim 3, antibodieswith strong anti-parasite activity will be cloned and expressed as human IgG for further characterization. In afollow-up study, these antibodies can be used for the identification of novel vaccine antigens. This antibodydiscovery platform is designed to identify the types of antibodies that should be elicited by a protective vaccine:antibodies with broad and potent anti-malaria activity. The methodology developed in this project is uniquelybased on screening of antibodies in functional assays and is thus fundamentally different from alternativemethods for dissecting B-cell immunity that have thus far been used in the field. This approach therefore hasthe potential to discover novel antibodies and antibody specificities. Ultimately, the results of this project willprovide much-needed insight into protective anti-malaria immunity and will accelerate vaccine design.