Placental malaria (PM) is a severe malaria complication in pregnancy, in areas with stable parasite transmission. It is a major cause of disease and death among pregnant women and their offspring. PM mainly affects primigravidae, as immunity is developed over successive pregnancies. This naturally acquired protection to PM is mediated by antibodies targeting a parasite antigen called VAR2CSA. Although VAR2CSA is a variable antigen, it has been previously demonstrated that the naturally acquired antibody response is generally broadly cross-reactive (meaning that serum from a multigravidae woman can recognize multiple VAR2CSA variants). However, the results of recently conducted trials of a VAR2CSA-based vaccine to prevent PM showed almost complete variant-specificity of the induced antibodies (only the particular VAR2CSA variant used for immunization was recognized), failing at mimicking what occurs during natural infection. This research project aims to resolve that conundrum by studying in detail the specificity and sequence characteristics of VAR2CSA-specific antibodies generated during natural infection. Specifically, I will collect B cells from Ghanaian women with naturally acquired PM immunity. I will then identify B cells producing antibodies that can react with a panel of recombinant protein variants selected to represent the global variation in VAR2CSA. I will then use an innovative technology (LIBRA-seq) to simultaneously identify the exact antigen specificity of each single VAR2CSA-reactive B-cell and importantly the exact sequence of the antibody encoded by the cell. The latter information will allow me to produce recombinant antibodies to be tested for cross-reactivity towards recombinant and native VAR2CSA variants, and for their ability to neutralize the function of VAR2CSA. The project has major potential to accelerate development of VAR2CSA-specific vaccines against PM.