Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region.

During pregnancy, Plasmodium falciparum-infected erythrocytes (IE) accumulate in the intervillous spaces of the placenta by binding to chondroitin sulfate A (CSA) and elicit inflammatory responses that are associated with poor pregnancy outcomes. Primigravidae lack immunity to IE that sequester in the placenta and thus are susceptible to placental malaria (PM). Women become resistant to PM over successive pregnancies as antibodies to placental IE are acquired. Here, we assayed plasma collected at delivery from Malian and Tanzanian women of different parities for total antibody levels against recombinant VAR2CSA antigens (FCR3 allele), and for surface reactivity and binding inhibition and opsonizing functional activities against IE using two CSA-binding laboratory isolates (FCR3 and NF54). Overall, antibody reactivity to VAR2CSA recombinant proteins and to CSA-binding IE was higher in multigravidae than in primigravidae. However, plasma from Malian gravid women reacted more strongly with FCR3 whereas Tanzanian plasma preferentially reacted with NF54. Further, acquisition of functional antibodies was variant dependent: binding inhibition of P. falciparum strain NF54 (P < 0.001) but not of the strain FCR3 increased significantly with parity, while only opsonizing activity against FCR3 (P < 0.001) increased significantly with parity. In addition, opsonizing and binding inhibition activities of plasma of multigravidae were significantly correlated in assays of FCR3 (r = 0.4, P = 0.01) but not of NF54 isolates; functional activities did not correlate in plasma from primigravidae. These data suggest that IE surface-expressed epitopes involved in each functional activity differ among P. falciparum strains. Consequently, geographic bias in circulating strains may impact antibody functions. Our study has implications for the development of PM vaccines aiming to achieve broad protection against various parasite strains.