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

Abstract

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.SummaryAfucosylated 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.

The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylated IgG1 in naive but not antigen-experienced vaccinees

“…This suggests an enhanced corresponding memory B cell response, which would be in line with stronger protection in this group (46)(47)(48). Similarly, a gradual increase in afucosylation has been observed with repeated natural immunizations to antigens displayed on the membrane of P. falciparum-infected red blood cells (23). This is in contrast to alloimmunization to the red blood cell RhD antigen, where the afucosylated response in hyperimmune donors is very stable over time (40).…”

“…The mRNA vaccine-induced presentation of the viral S protein on the membrane of host cells mimics the S protein presentation during natural SARS-CoV-2 infections. Enveloped viruses, attenuated enveloped viral vaccines, but also P. falciparum-infected erythrocytes and alloantigens on blood cells express antigens on host cells and induce persistent afucosylated IgG responses (2,(22)(23)(24)(25)40). Although we previously found afucosylated IgG responses to be associated with strong pro-inflammatory responses in critically ill COVID-19 patients (1,2), this type of response seems to be protective in HIV infections (24) and malaria (23).…”

“…The common characteristic of such responses is that the corresponding pathogenspecific antigens are generally expressed on the host cell membrane, unlike most foreign antigens. Intriguingly, pathogen-specific afucosylated IgG1 responses seem to be protective in malaria (23) and HIV (24), but can, in turn, cause massive inflammation via FcγRIII-mediated pathologies in patients with severe dengue fever (25) and have been shown to precede severe COVID-19 (1)(2)(3)26).…”

“…Afucosylated IgG has an enhanced binding to FcγRIII, resulting in increased cytokine production and cellular responses, such as Ab-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC) (6,7,17). In healthy conditions, the majority of IgG found in plasma is fucosylated (~94%) (18,19), but afucosylated, antigen-specific IgG responses have been described in various pathologies, including alloimmune responses to blood cells (20)(21)(22), as well as immune responses to Plasmodium (P) falciparum antigens expressed on erythrocytes (23) and to foreign proteins of enveloped viruses, including human immunodeficiency virus (HIV) (24), dengue virus (25), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (2,3). The common characteristic of such responses is that the corresponding pathogenspecific antigens are generally expressed on the host cell membrane, unlike most foreign antigens.…”

“…This includes those of recombinant hepatitis B virus (HBV) and P. falciparum-proteins. On the contrary, when expressed in their natural context on host cells, afucosylated IgG responses have been observed in HBV and malaria (2,23). This led us to the hypothesis that antigen presentation at the surface of host cells, possibly together with host co-factors, is required for the induction of afucosylated IgG responses (2).…”