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ItemHigh Avidity Antibodies to VAR2CSA: Are They Associated with Protection from Placental Malaria in a Low Transmission Setting?([Honolulu] : [University of Hawaii at Manoa], [December 2015], 2015-12)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.
ItemThe Specificity of Naturally Acquired Antibodies that Bind to the Surface of VAR2CSA-Expressing P. Falciparum Infected Erythrocytes([Honolulu] : [University of Hawaii at Manoa], [December 2015], 2015-12)Placental malaria (PM) caused by Plasmodium falciparium is a major health problem affecting both the mother and fetus. Previous studies showed that high anti-VAR2CSA IgG levels improve pregnancy outcome, e.g., increase birth weight, reduce anemia, lower placental parasitemia, and prevent drug treatment failures. VAR2CSA has 6 DBL domains. Pregnant women produce antibodies (Ab) that bind to the surface of CSA binding IE. It is not clear if these Ab bind to one or multiple DBL domains. The goal of this study was to determine the specificity of naturally acquired Ab that bind to CS2 IE. In our study, clinical information and archival plasma samples collected between 1996 -2001 at delivery from 1,377 pregnant Cameroonian women living in Yaoundé (low transmission) were used. Since the samples were collected prior to implementation of intermittent preventive treatment and insecticide-treated bed nets, natural immunity determined the presence or absence of PM. Plasma from women who were PM- and PM+ of different gravidities were screened for Ab to full length VAR2CSA (FV2) and other DBL domains using a bead-based multiplex assay. The results identified which DBL domains each woman recognized. Then, a subset of samples was tested for Ab binding to the surface of CS2 IE (express VAR2CSA) and to 3D7 IE (non CSA-binding phenotypes). IE were incubated with plasma, then anti-human IgG FITC, and the amount of fluorescence per cell surface area was determined by FACS. In this study using 100 samples with different levels of Ab to FV2, a Significant correlation between Ab to FV2 and cell surface staining intensity was obtained (r = 0.62; P< .0001: Spearman Correlation) and levels of reactivity to the different DBL domains recognized by each woman was reported. Most domains showed a modest correlation of Ab levels and CSS. DBL1( Corr=0.42, P<.0001), DBL1+2(Corr=0.49, P<.0001), DBL2(Corr=0.23, P=0.025), ID1 D2a(Corr=0.37, P=0.0002), DBL3(Corr=0.48, P<.0001), DBL4(Corr=0.45, P<.0001 ), DBL5(Corr=0.45, P<.0001 ), and DBL6 (Corr=0.49, P<.0001 )
ItemCombined Treatment of a Novel Adenosine Analogue Inhibitor and Histone Deacetylase Inhibitor Represents an Immunotherapy Strategy to Ameliorate West Nile Virus Infection([Honolulu] : [University of Hawaii at Manoa], [May 2015], 2015-05)