VAR2Mab

Although malaria vaccine has long been a research priority, little progresses were made over the last decades. One major hurdle that could explain the failure of malaria vaccines to date is that the malaria parasite has an extraordinary ability to evade the Host immune system. Placental malaria is linked to the massive accumulation of Plasmodium falciparum-infected erythrocytes (IEs) in the placenta, leading to maternal as well as fetal and infant mortality. Placental IEs bind to chondroitin sulfate A (CSA) to sequester in the placenta, and women become resistant over successive pregnancies as they acquire antibodies that block IEs adhesion to CSA. The P. falciparum-derived protein VAR2CSA is the parasite ligand mediating IEs binding to CSA and is the target of antibodies associated to protection. We recently reported the safety and immunogenicity of a VAR2CSA-derived PM vaccine (PRIMVAC) in a Phase I clinical trial. The recent development of human monoclonal Abs (humAbs) has expanded our ability to understand the fine specificity of naturally acquired and artificially induced (i.e., through vaccination) protective Abs that can be used to inform the design of next generation malaria vaccines and develop new therapeutics. In this project we aim to isolate humAbs to VAR2CSA from multigravid women with naturally acquired immunity to VAR2CSA and from malaria naïve women vaccinated with the PRIMVAC vaccine. We hypothesize that high affinity humAbs that recognize strain-transcending VAR2CSA epitopes will block IEs binding to CSA and recognize epitopes that facilitate opsonic phagocytosis/cytotoxicity and Ab cooperativity. Further, we aim to identify the epitopes recognized by these humAbs to design second-generation placental malaria vaccines and therapeutics.