VAR2CSA-specific IgG and IgM antibodies are markers of exposure and protection against adverse malaria pregnancy outcomes

Background: Placental malaria is caused by the binding of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) protein VAR2CSA, found on the surface of infected erythrocytes, to placental tissue. Complications include maternal anaemia, low birth weight, small for gestational age and preterm delivery. Acquisition of antibodies against VAR2CSA during pregnancy has been linked to immunity against infection. 

Methods: Pregnant Malawian women were enrolled at their first antenatal care visit at 16–28 weeks’ gestation into a trial of malaria prevention. Women with malaria infection at enrolment (n = 321) or any later point in pregnancy (n = 145) were selected. The IgG and IgM plasma levels against the VAR2CSA DBL1X-ID2a domain were measured at enrolment and delivery. Associations between the DBL1X-ID2a VAR2CSA-specific IgG and IgM antibody levels at enrolment or delivery and low birth weight, small for gestational age, maternal anaemia at delivery, and preterm delivery were assessed using logistic regression with confounder adjustment. 

Result: Women with malaria infection at enrolment had higher antibody levels to DBL1X-ID2a than uninfected women, and these declined from enrolment to delivery. There were no significant associations between the IgG antibody level measured at enrolment and the birth outcomes of interest, but the IgG antibody level at delivery in women uninfected at enrolment was associated with a lower risk of low birth weight, adjusted odds ratio (aOR) 0.43 (95% CI 0.19–0.97) p = 0.04. Additionally, in women infected at enrolment, one log higher IgM antibodies to DBL1X-ID2a VAR2CSA at enrolment were associated with a significant 23% decrease in maternal anaemia at delivery, aOR 0.77 (95% CI 0.60–0.99), p = 0.04. 

Conclusion: VAR2CSA-specific IgG and IgM antibodies are markers of malaria infection and protection against placental malaria outcomes.