AfucosylatedPlasmodium falciparum-specific IgG is induced by infection but not by subunit vaccination

IgG specific for members of the Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1) family, which mediates receptor- and tissue-specific sequestration of infected erythrocytes (IEs), is a central component of naturally acquired malaria immunity. PfEMP1-specific IgG is thought to protect via inhibition of IE sequestration, and through IgG-Fc Receptor (FcγR) mediated phagocytosis and killing of antibody-opsonized IEs. The affinity of afucosylated IgG to FcγRIIIa is elevated up to 40-fold compared to fucosylated IgG, resulting in enhanced antibody-dependent cellular cytotoxicity. Most IgG in plasma is fully fucosylated, but afucosylated IgG is elicited in response to enveloped viruses and to paternal alloantigens during pregnancy. Here we show that naturally acquired PfEMP1-specific IgG is likewise markedly afucosylated in a stable and exposure-dependent manner, and efficiently induces FcγRIIIa-dependent natural killer (NK) cell degranulation. In contrast, immunization with a soluble subunit vaccine based on VAR2CSA-type PfEMP1 resulted in fully fucosylated specific IgG. These results have implications for understanding natural and vaccine-induced antibody-mediated protective immunity to malaria. Summary Afucosylated IgG has enhanced Fc-receptor affinity and functionality, and is formed specifically against membrane proteins of enveloped viruses. We show that this also applies to Plasmodium falciparum erythrocyte membrane-specific IgG induced by natural infection, but not by soluble PfEMP1 vaccination.