Can complement fix placental malaria?

Abstract

The problem of placental malaria Placental malaria (PM) is a deadly public health problem caused by the human parasite Plasmodium falciparum, and this scourge will get worse as existing control measures lose potency. Our understanding of PM pathogenesis suggests a vaccine is feasible, but first-generation candidates yielded only modest variant-specific activity in early trials. In this issue of BMC Medicine, Opi and colleagues provide evidence for a heretofore unrecognized mechanism of protective immunity, whereby the neutralizing activity of antibody against PM parasites is enhanced by fixing the complement component C1q [1]. Recent estimates [2] hold that up to 50,000 maternal deaths and 200,000 stillbirths result from PM in Africa annually, with additional mortality during infancy related to preterm and low birthweight deliveries. Despite public health advances including chemoprevention using intermittent sulfadoxine-pyrimethamine (SP) treatments, as well as insecticide-treated bednets, the terrible toll on mothers and their offspring continues. Deaths will increase as parasite resistance to SP intensifies and spreads. The underlying cause of PM is well-established: P. falciparum-infected erythrocytes (IEs) adhere to receptors, mainly chondroitin sulfate A (CSA), and sequester in intervillous spaces (maternal blood) of the placenta, eliciting an inflammatory response associated with poor maternal and fetal outcomes. The parasite ligand for CSA, VAR2CSA, is a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of variant surface antigens. Its large size and extensive sequence variation make VAR2CSA a challenging target for vaccine developers, and insights into protective antibodies and epitopes are needed to focus immunogen design. Nature suggests the solution to the PM problem. Over successive pregnancies, pregnant women in areas of endemicity develop resistance and simultaneously acquire antibodies against placental IEs, including antibody that blocks IE binding to CSA [3] or mediates IE opsonization/phagocytosis [4]. These functional antibodies are believed to target VAR2CSA, and antibodies to VAR2CSA increase over successive pregnancies, but the association of VAR2CSA antibodies to improved clinical outcomes has been inconsistent [5].