Acquisition and Decay of Antibodies to Pregnancy‐Associated Variant Antigens on the Surface ofPlasmodium falciparum–Infected Erythrocytes That Protect against Placental Parasitemia

Abstract

Otherwise clinically immune women in areas endemic for malaria are highly susceptible to Plasmodium falciparum malaria during their first pregnancy. Pregnancy-associated malaria (PAM) is characterized by placental accumulation of infected erythrocytes that adhere to chondroitin sulfate A (CSA). Susceptibility to PAM decreases with increasing parity, apparently due to acquisition of antibodies directed against the variant surface antigens (VSAs) that mediate the adhesion to CSA (VSA(CSA)). This study found that levels of VSA(CSA)-specific antibodies depend on endemicity, that anti-VSA(CSA) IgG is acquired during gestation week 20, and that plasma levels of the antibodies decline during the postpartum period. There is evidence that VSA(CSA)-specific antibodies are linked to placental infection and that high antibody levels contribute to the control of placental infection by inhibiting parasite adhesion to CSA. Data suggest that VSA(CSA) is a target for vaccination against PAM.

Low antibody responses to variant surface antigens of Plasmodium falciparum are associated with severe malaria and increased susceptibility to malaria attacks in Gabonese children.

“…As others have convincingly shown, such "gaps" in recognition are associated with malaria episodes in individuals with low immunity and also with P. falciparum infections in pregnant women. 4,32,33,48,49 The level of anti-VSA antibodies, furthermore, has been shown to correlate with adhesion inhibition, itself a surrogate marker of protection against P. falciparum infection. 49,50 Thus, we believe the data presented here provide further evidence for an immunologic basis to the explanation of the radically different susceptibility to malaria in the two groups of children in our study.…”

“…4,32,33,48,49 The level of anti-VSA antibodies, furthermore, has been shown to correlate with adhesion inhibition, itself a surrogate marker of protection against P. falciparum infection. 49,50 Thus, we believe the data presented here provide further evidence for an immunologic basis to the explanation of the radically different susceptibility to malaria in the two groups of children in our study. We showed, in an earlier assessment of cell-mediated immune responses in these same children, that parasite antigen-specific interferon-␥ responses differed significantly between the groups with either mild or severe malaria.…”

Changing Trends inP. falciparumBurden, Immunity, and Disease in Pregnancy

“…Moreover, levels of IgG antibodies against CS2 were increased in women with qPCR-positive P. falciparum infection at delivery. 16,17 These results indicate a close relationship between antibody levels and the intensity of malaria transmission [16][17][18][34][35][36] and suggest that antibodies against VAR2CSA may be a marker for cumulative exposure to the parasite during pregnancy. 19 More important, this study shows that 5 years of a marked decline in the prevalence of malaria was accompanied by reductions in levels of IgG antibodies against CS2 parasites by a factor of 2.8 and by reductions in IgG antibodies against antigens that are not specific to pregnancy, as well as by an increase in the geometric mean of parasite densities and a larger adverse effect of these infections on maternal hemoglobin levels and the weight of newborns.…”

Cytoadhesion of Plasmodium falciparum-infected erythrocytes and the infected placenta: a two-way pathway

“…Primigravidae have a much higher susceptibility to maternal malaria than multigravidae, because the antibodies acquired after multiple pregnancies are associated with a reduction in the number of IE in the placenta (34). In addition, higher levels of these CSA adhesion-blocking antibodies are correlated with less pronounced maternal anemia and with higher birth weight for babies born at term (35,36).…”

“…The first evidence that it might be possible to develop an anti-PAM vaccine was provided by the study of Fried and Duffy (9,35) and Staalsoe et al (34,36) showing that multiparous women were less susceptible to PAM than women in their first pregnancy, that infected women developed high levels of adhesion-blocking antibodies against PAM parasites after several pregnancies (9,34) and that these antibodies were associated with attenuation of the clinical outcome of PAM. Antibodies against var2 CSA parasites have also been shown to crossreact with genetically different P. falciparum strains (49).…”