High Avidity Antibodies to VAR2CSA: Are They Associated with Protection from Placental Malaria in a Low Transmission Setting?

M.S. University of Hawaii at Manoa 2015.Includes bibliographical references.Placental malaria is characterized by the sequestration of Plasmodium falciparum infected erythrocytes in the intervillous space of the placenta. Sequestration is mediated by the binding of a parasite membrane protein called VAR2CSA to Chondriotin Sulfate A on the surface of placental syncytiotrophoblasts. The presence of ≥ 35% high avidity antibodies (Ab) to VAR2CSA early in pregnancy correlates with the absence of placental malaria at delivery in a high transmission setting. Little is known about high avidity Ab to VAR2CSA in low transmission areas, and if one or multiple pregnancies are required to produce such Ab. Therefore, blood samples obtained at delivery between 1995 and 2001from women living in Yaoundé, Cameroon (low transmission setting) were used in this study. The plasma samples collected prior to use of chemoprophylaxis (IPT) and bed nets, so natural immunity determined presence/absence of placental malaria. These samples were screened for IgG Ab to Full Length VAR2CSA (FV2) using a bead-based immunoassay and 494 samples were identified as being Ab-positive. The percentage of strong binding (high avidity) IgG equals the amount of Ab that remain bound to FV2 after 30 minutes of incubation with 3M NH4SCN. Results showed that 178 of the 494 women had ≥35% high avidity Ab at delivery. Ab avidity increased significantly between the 1st and 2nd pregnancies however, it remained constant thereafter. After adjusting for age and malaria status, a significant increase in avidity with gravidity was found (P=0.0008). Avidity increased gradually, with only a 0.9% increase per pregnancy. A higher mean avidity was found in PM-negative compared to PM-positive secundigravidae (P=0.022), but no difference was seen between PM+ and PM- in the other gravidity groups. A modest correlation between high avidity Ab to FV2 and Ab levels. Affinity maturation peaked at G2 and tended to be almost stable with subsequent pregnancies. The Ab specificity of the DBL domains suggest the N-terminal may have a role in the production of high avidity Ab. Ab avidity may serve as an important correlate of protection, hence can be considered an important marker for the assessment of the efficacy of VAR2CSA vaccine candidate

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