Comparison of the specificity of antibodies to VAR2CSA in Cameroonian multigravidae with and without placental malaria: a retrospective case–control study

Abstract

BackgroundAntibodies (Ab) to VAR2CSA prevent Plasmodium falciparum-infected erythrocytes from sequestrating in the placenta, i.e., prevent placental malaria (PM). The specificity of Ab to VAR2CSA associated with absence of PM is unknown. Accordingly, differences in the specificity of Ab to VAR2CSA were compared between multigravidae with and without PM who had Ab to VAR2CSA.MethodsIn a retrospective case–control study, plasma collected from Cameroonian multigravidae with (n = 96) and without (n = 324) PM were screened in 21 assays that measured antibody levels to full length VAR2CSA (FV2), individual VAR2CSA DBL domains, VAR2CSA domains from different genetic backgrounds (variants), as well as proportion of high avidity Ab to FV2.ResultsMultigravidae with and without PM had similar levels of Ab to FV2, the six VAR2CSA DBL domains and different variants, while the proportion of high avidity Ab to FV2 was significantly higher in women without PM at delivery (p = 0.0030) compared to women with PM. In a logistic regression model adjusted for gravidity and age, the percentage of high avidity Ab to FV2 was associated with reduced likelihood of PM in multigravidae. A 5 % increase in proportion of high avidity Ab to FV2 was associated with a nearly 15 % lower likelihood of PM.ConclusionAb avidity to FV2 may be an important indicator of immunity to PM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-1023-6) contains supplementary material, which is available to authorized users.

Antibody responses to the full-length VAR2CSA and its DBL domains in Cameroonian children and teenagers

“…Previous study by Gnidehou et al tested children’s plasma samples for Ab to recombinant ID1–ID2, DBL3x and DBL5ɛ in Colombian non-pregnant individuals living in P. falciparum and P. vivax transmission area [35]. In this Cameroonian cohort of children, specificity of IgG to VAR2CSA appeared to be different from that of MG, with children more likely responding to DBL2, DBL3 and DBL4, while in MG DBL5 is most immunogenic, followed by DBL3 [36, 37, 47]. These differences in responses are important in the light of correlates of protection from PM.…”

“…These differences in responses are important in the light of correlates of protection from PM. Correlates of protection from PM include breadth of responses to multiple VAR2CSA domains, high avidity Ab to FV2 and high levels of Ab to DBL1-2, DBL3, DBL1-3x [37, 47–50]. In addition, it is not clear how long Ab to DBL2 and DBL4 persist.…”

“…Recombinant VAR2CSA DBL domains used in this study were described previously and include: DBL1 3D7, DBL1 7G8, ID1–ID2a FCR3, DBL2 FCR3, DBL3 FCR3, DBL3 7G8, DBL3 A4/FCR3, DBL4 FCR3, DBL4 7G8, DBL5 FCR3, DBL5 3D7, DBL5 7G8, DBL6 FCR3, and full-length VAR2CSA (FV2) FCR3 [36, 37]. Other non-pregnancy specific antigens included were recombinant AMA-1 (3D7 strain) expressed in yeast provided by the Malaria Vaccine Development Branch (MVDB), NIH; recombinant EBA-175 RII expressed in yeast obtained from Science Applications International Corp., Frederick, MD; recombinant MSP-1 42 (3D7 strain) expressed in Escherichia coli (MVDB); recombinant MSP-2 (FC27 strain) (MVDB); recombinant MSP-3 C-terminal region expressed in E. coli provided by P. Druihle, Institute Pasteur, Paris, France.…”

“…IgG to malaria antigens was measured using MAP assay as described before [37]. Modification includes the use of magnetic plate separator instead of vacuum manifold (Luminex, Austin, Texas, Cat# CN-0269-01) and a MAGPIX reader instead of Luminex 100 instrument (EMD Millipore, Billerica, MA).…”

“…Ab to VAR2CSA are thought to be pregnancy specific; however, studies showed that they can also be detected in non-pregnant individuals including men and children [33–37]. It is assumed the number of IE expressing the same var gene must reach a high enough levels before the host can begin producing a detectable Ab response to each variant.…”