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. 2012 Apr;80(4):1479-90.
doi: 10.1128/IAI.00071-12. Epub 2012 Feb 13.

High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission

Yeung L Tutterrow  1 , Marion Avril, Kavita Singh, Carole A Long, Robert J Leke, Grace Sama, Ali Salanti, Joseph D Smith, Rose G F Leke, Diane W Taylor
Affiliations

High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission

Yeung L Tutterrow et al. Infect Immun. 2012 Apr.

Abstract

Placental malaria, caused by sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, is associated with increased risk of maternal morbidity and poor birth outcomes. The parasite antigen VAR2CSA (variant surface antigen 2-chondroitin sulfate A) is expressed on infected erythrocytes and mediates binding to chondroitin sulfate A, initiating inflammation and disrupting homeostasis at the maternal-fetal interface. Although antibodies can prevent sequestration, it is unclear whether parasite clearance is due to antibodies to a single Duffy binding-like (DBL) domain or to an extensive repertoire of antibodies to multiple DBL domains and allelic variants. Accordingly, plasma samples collected longitudinally from pregnant women were screened for naturally acquired antibodies against an extensive panel of VAR2CSA proteins, including 2 to 3 allelic variants for each of 5 different DBL domains. Analyses were performed on plasma samples collected from 3 to 9 months of pregnancy from women living in areas in Cameroon with high and low malaria transmission. The results demonstrate that high antibody levels to multiple VAR2CSA domains, rather than a single domain, were associated with the absence of placental malaria when antibodies were present from early in the second trimester until term. Absence of placental malaria was associated with increasing antibody breadth to different DBL domains and allelic variants in multigravid women. Furthermore, the antibody responses of women in the lower-transmission site had both lower magnitude and lesser breadth than those in the high-transmission site. These data suggest that immunity to placental malaria results from high antibody levels to multiple VAR2CSA domains and allelic variants and that antibody breadth is influenced by malaria transmission intensity.

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Figures

Fig 1
Fig 1
Prevalence of antibodies to VAR2CSA domains in women living in the high-transmission site of Ngali II. Sera collected longitudinally from 39 women (6 ± 1.2 samples per woman) between 3 and 9 months of pregnancy were screened for IgG Ab against 13 variants of VAR2CSA. Antibody results were grouped into 4 categories: Ab negative (less than the mean + 2 SD of the results for 20 adult males living in Ngali II); low (>cutoff but <5,000 MFI), intermediate (5,000 to 10,000 MFI), and high (>10,000 MFI). The total number of data points per month of pregnancy ranged from 19 to 37 serum samples. MSP-142 and AMA1 were included as non-VAR2CSA controls. Note: women with intermediate and high Ab levels were considered to have strong antibody responses. Specific cutoffs were as follows: DBL1 7G8-Pp (1,247 MFI), DBL1 3D7-Pp (1,122 MFI), DBL1 FCR3-Pp (438 MFI), DBL3 7G8-Pp (884 MFI), DBL3 FCR3-BV (1,207 MFI), DBL3 FCR3-Ec (768 MFI), DBL4 7G8-Pp (534 MFI), DBL4 FCR3-BV (3,490 MFI), DBL4 FCR3-Pp (502 MFI), DBL5 7G8-Pp (893 MFI), DBL5 FCR3-BV (542 MFI), DBL5 3D7-Pp (772 MFI), DBL6 7G8-Pp (3,202 MFI), DBL6 FCR3-BV (1,725 MFI), DBL6 FCR3-Pp (1,370 MFI), and DBL1+2 FCR3-BV (1,584 MFI). MFI, median fluorescence intensity.
Fig 2
Fig 2
Prevalence of antibodies to different VAR2CSA domains in women living in the low-transmission site of Yaoundé. Sera collected longitudinally from 50 women (6 ± 1.2 samples per woman) were screened for IgG antibodies against the 13 variant domains of VAR2CSA. Ab values were grouped into 4 categories as described in the Fig. 1 legend, using a cutoff of the mean + 2 SD of the results for 20 adult males living in Yaoundé. The number of data points per month of pregnancy ranged from 39 to 46 serum samples. Specific cutoffs were as follows: DBL1 7G8-Pp (1,046 MFI), DBL1 3D7-Pp (854 MFI), DBL1 FCR3-Pp (425 MFI), DBL3 7G8-Pp (419 MFI), DBL3 FCR3-BV (598 MFI), DBL3 FCR3-Ec (288 MFI), DBL4 7G8-Pp (184 MFI), DBL4 FCR3-BV (1,620 MFI), DBL4 FCR3-Pp (427 MFI), DBL5 7G8-Pp (408 MFI), DBL5 FCR3-BV (187), DBL5 3D7-Pp (369 MFI), DBL6 7G8-Pp (1,636 MFI), DBL6 FCR3-BV (751 MFI), DBL6 FCR3-Pp (1,089 MFI), and DBL1+2 FCR3-BV (626 MFI). MFI, mean fluorescent intensity.
Fig 3
Fig 3
Correlation between antibody levels and absence of placental malaria in women in Ngali II. Mean antibody levels throughout the course of pregnancy were compared between women who were placental malaria positive (PM+) at delivery (n = 14) and those who were placental malaria negative (PM−) (n = 13) using multilevel polynomial regression analysis. Significant associations and their corresponding P values are shown. Individual data points are the mean ± standard error of the mean (SEM) for a minimum of 7 values.
Fig 4
Fig 4
Breadth of IgG response to the 5 DBL domains and 13 variants stratified by placental malaria status. At each month of pregnancy, the maximal number of DBL domains and strain variants each woman had Ab to was determined. The breadth of the response was compared between women who were placental malaria negative (PM−) and placental malaria positive (PM+). Results are presented as mean ± SEM. Maximum number of domains is 5; maximum number of variants is 13. P values are based on multilevel polynomial regression analysis.
Fig 5
Fig 5
Comparison of Ab levels in primigravidae and multigravidae living in Ngali II. Antibodies to DBL3, DBL4, DBL5, and DBL6 were compared between primigravidae (PG) and multigravidae (MG) who were placental malaria positive (PM+) and placental malaria negative (PM−). All PM− women in Ngali II were MG (n = 13). Similar Ab levels were found between PM+ PG (n = 7) and MG (n = 7). The same trend was observed with the other strain variants of DBL3, DBL4, and DBL5. The arrow on the y axis and associated horizontal dotted line indicate the cutoff value for seropositivity (mean ± 2 SD of the results for male controls).
Fig 6
Fig 6
Influence of gravidity on the breadth of IgG responses. The breadth of Ab responses to VAR2CSA DBL domains and variants during pregnancy were compared between primigravidae (PG) and multigravidae (MG) who were placental malaria negative (PM−) and placental malaria positive (PM+). Results are represented as mean ± SEM.
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