Malaria in pregnancy is responsible for ~900,000 deliveries of low birth weight babies, and ~100,000 still births in Africa alone. Pregnant women, despite lifetime malaria exposure, are more susceptible to Plasmodium falciparum malaria than their non-pregnant counterparts, due to the ability of parasites to sequester in the placenta via adhesion to a pregnancy-associated P. falciparum erythrocyte membrane protein-1 (PfEMP-1) variant surface antigen that is upregulated during pregnancy . Recent clinical studies have shown an association between the presence of antibody to a unique antigen on infected erythrocytes called VAR2CSA, which belongs to the PfEMP-1 family, and protection from placental malaria. The mechanisms of how this antibody protects against malaria is not understood .
This project aims to explore the antibody response to VAR2CSA, exploring the functional and structural properties of these antibodies in order to identify the mechanisms behind protection. Recent studies have shown that malaria-specific IgG3 is even more associated with malaria immunity than any other IgG subclasses . IgG3 immunogenic properties might explain why it is more protective compared to other IgG subclasses: its higher affinity for complement component C1q and FcγRs, the longer flexible hinge region, that are characteristics which enhance opsonisation of malaria-infected erythrocytes and promotion of effector functions such antibody mediated activation of Natural Killer (NK) cells. Engagement of antibody opsonized antigens or infected erythrocytes by NK cells via Fc receptors can produce pro-inflammatory cytokines and mediate antibody dependent cellular cytotoxicity. However, it is an understudied potentially mechanism of protection in malaria infections.
Understanding the mechanisms behind enhanced functional IgG3 activity and antibody mediated NK cell activation against VAR2CSA should provide vital information to guide the rational development of future antibody based vaccines to prevent complications of pregnancy-related malaria.