"Malaria continues to be the most important parasitic disease with as many as one million deaths annually. Despite these sobering figures, there is a decline in the burden of malaria that has stimulated researchers to set an agenda for worldwide malaria eradication. Malaria transmission blocking vaccines (MTBV) that induce antibody responses that prevent the transmission of malaria from man to mosquito are high on the priority of this research agenda. However, the number of MTBV candidates has remained practically unaltered in the last 20 years and none have successfully entered clinical trials. This proposal aims to provide a leap forward in the identification of novel MTBV target antigens and unravelling the immune signature of naturally acquired transmission blocking immunity (TBI).For this purpose, samples will be used that have been collected in large-scale epidemiological studies, where they were included in mosquito feeding assays in the field to confirm their transmission potential. TBI will be confirmed by adding purified IgG to cultured gametocytes in the highly standardized standard membrane feeding assay (SMFA) at the Nijmegen Centre for Molecular Life Sciences of the Radboud University, Nijmegen. Functional TBI will be quantified as the reduction in the proportion of infected mosquitoes compared to malaria naïve control IgG. Samples with and without evidence for TBI will be matched for cumulative malaria exposure and used for immune profiling using a recently developed protein microarray. This protein microarray contains >20% of the P. falciparum 5,400-protein proteome and more than 300 uncharacterized sexual stage specific proteins that may be involved in TBI. By combining novel immunological, entomological and molecular tools, our approach will plausibly identify novel targets for TBI and lead to new horizons for MTBV development."