Plasmodium falciparum VAR2CSA-Specific IgG Subclass Responses Reflect Protection Against Low Birth Weight and Pregnancy-Associated Malaria

Abstract

Sequestration of Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen in the placenta results in poor pregnancy outcomes, including low birth weight and maternal anemia. Antigen-specific antibody-mediated immunity is acquired during successive pregnancies. Thus, evaluating VAR2CSA-specific IgG profiles among pregnant women will increase knowledge on the immunological mechanisms associated with protection, and help in the development of VAR2CSA-based placental malaria vaccines. Using the PAMVAC candidate vaccine antigen, we assessed anti-VAR2CSA IgG subclass responses of a cohort of pregnant Beninese, and analyzed their relationships with pregnancy outcomes. Cytophilic IgG1 and IgG3 responses were the most frequent, with prevalences ranging from 28% (IgG3) up to 50% (IgG1). Elevated levels of VAR2CSA-specific total IgG and cytophilic IgG3 during pregnancy were consistently associated with higher birth weights, whilst high levels of IgG4 were associated with a reduced risk of placental infections. This suggests that protective anti-VAR2CSA IgG responses are coordinated between both cytophilic and non-cytophilic antibodies.

Keywords: IgG subclasses; IgG3; IgG4; VAR2CSA; malaria; pregnancy.

Figure 1

IgG subclass profile to ID1-ID2a recombinant protein from pregnant women followed during the course of pregnancy (inclusion, antenatal visits (ANV) and delivery). (A) The distribution of IgG subclasses. Shown are IgG subclasses antibody levels (median and IQR) in arbitrary units. (B) IgG subclass seroprevalence. The profile of IgG subclasses clearly shows a cytophilic IgG’s (IgG1 and IgG3) are the predominant IgGs while low prevalence of non-cytophilic IgG’s (IgG2 and IgG4) were also observed.