Malaria affects nearly one-half of the world's population and causes more than 1.2 million deaths each year. Immunologically immature children bear the greatest burden of morbidity and mortality, and represent a key target group for vaccine development efforts. Historically, selection of malaria vaccine candidates has been empiric, unsystematic, and limited to a small portfolio. Therefore, our laboratory established a transformative high-throughput platform to screen a Plasmodium falciparum complementary DNA bacteriophage library that displays potentially the entire proteome of blood stage parasites. Our laboratory previously identified 10 immunoreactive antigens that were uniquely recognized by antibodies in plasma from resistant but not susceptible children. There is evidence that at least three of these antigens (MSP-3, MSP-7 and RAMA) as well as a novel protein with unknown function (PfLSP-1) have protective functions in pre-clinical or clinical studies. The objective ofthe current proposal is to fully characterize an additional vaccine candidate. Clone 10 using the infrastructure and expertise ofthe Centerfor International Health Research at Rhode Island Hospital/Brown University and the University of Rhode Island. We hypothesize that Clone 10 represents a novel blood-stage malaria target that induces a robust and protective immune response in children. We will assess its potential effectiveness as a vaccine using state-of-the-art in vitro and translational techniques that were successful in our hands previously. Specifically, we will characterize the role of Clone 10 in red blood cell invasion and schizogony by performing immunolocalization studies on infected red blood cells, and invasion/growth inhibition assays to determine the role of anti-Clone 10 antibodies in mediating resistance. We will assess whether the findings can be translated into a model of lethal murine malaria using Clone 10- homologue DNA and protein subunit vaccines derived from Plasmodium berghei (ANKA) to induce immunity. We will then validate the generalizability of protective human immune responses against Clone 10 and other candidate antigens in an independent cohort of Tanzanian children, and investigate potential single nucleotide polymorphisms in Clone 10 from 20 P. falciparum field isolates from Tanzania.
Malaria affects almost one-half ofthe world's population and causes high mortality in African children. This research aims to develop an effective new malaria vaccine that targets the blood stage of malaria in children. A candidate malaria antigen identified by a clinically-driven whole proteomic screen will be fully characterized using in vitro functional assays, animal models of infection and correlates of human protection.
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