VAR2CSA Serology to Detec<i>t Plasmodium falciparum</i> Transmission Patterns in Pregnancy

Fonseca, Ana Maria; González, Raquel; Bardají, Azucena; Jairoce, Chenjerai; Rosario, Maria; Jiménez, Alfons; Quintó, Llorenç; Cisteró, Pau; Valá, Anifa; Sacoor, Charfudin; Gupta, Himanshu; Hegewisch-Taylor, Jennifer; Brew, Joe; Ndam, Nicaise Tuikue; Kariuki, Simon; López, Marta; Dobaño, Carlota; Chitnis, Chetan E.; Ouma, Peter; Ramharter, Michael; Abdulla, Salim; Aponte, John J.; Massougbodji, Achille; Briand, Valérie; Mombo-Ngoma, Ghyslain; Desai, Meghna; Cot, Michel; Nhacolo, Arsénio; Sevene, Esperança; Macete, Eusébio; Menéndez, Clara; Mayor, Alfredo

doi:10.3201/eid2510.181177

Cited by 12 publications

(9 citation statements)

References 29 publications

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“…This may reflect the fact that the responses to different VARCSA domains were generally highly correlated, as revealed by their clustering together in the center of our network analysis, or it might be because of the longevity of antibody that promotes ADCP of IE compared to that of antibody responses to recombinant proteins ( Teo et al, 2014 ; Teo et al, 2015 ; Chandrasiri et al, 2014 ). Antibody to VAR2CSA recombinant proteins, and particularly to specific VAR2CSA peptides, appears to be a good correlate of exposure and transmission intensity ( Fonseca et al, 2019 ), but these responses appear to be less useful as correlates of protection.…”

Section: Discussionmentioning

confidence: 99%

Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria

Aitken

Damelang

Ortega-Pajares

et al. 2021

eLife

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Background:Plasmodium falciparum causes placental malaria, which results in adverse outcomes for mother and child. P. falciparum-infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease. The objective of this study was to develop a prediction model using antibody features that could identify women protected from placental malaria.Methods:We used a systems serology approach with elastic net-regularized logistic regression, partial least squares discriminant analysis, and a case-control study design to identify naturally acquired antibody features mid-pregnancy that were associated with protection from placental malaria at delivery in a cohort of 77 pregnant women from Madang, Papua New Guinea.Results:The machine learning techniques selected 6 out of 169 measured antibody features towards VAR2CSA that could predict (with 86% accuracy) whether a woman would subsequently have active placental malaria infection at delivery. Selected features included previously described associations with inhibition of placental binding and/or opsonic phagocytosis of infected erythrocytes, and network analysis indicated that there are not one but multiple pathways to protection from placental malaria.Conclusions:We have identified candidate antibody features that could accurately identify malaria-infected women as protected from placental infection. It is likely that there are multiple pathways to protection against placental malaria.Funding:This study was supported by the National Health and Medical Research Council (Nos. APP1143946, GNT1145303, APP1092789, APP1140509, and APP1104975).

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Section: Discussionmentioning

confidence: 99%

Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria

Aitken

Damelang

Ortega-Pajares

et al. 2021

eLife

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“…Immunoglobulin G (IgG) eluted from 5760 available DBS were quantified using the xMAP technology and the Luminex 100/200 System ( https://www.luminexcorp.com ) [ 19 ]. The multiplex suspension array panel included VAR2CSA antigens (Duffy binding-like recombinant domains DBL3-4 [ 20 ] as well as peptides targeting the NTS region [P1] and ID1 [P8 and PD] [ 19 ]), non-pregnancy specific antigens (19-kDa fragment of the merozoite surface protein-1 [MSP1 19 ] [ 21 ], region II/F2 of erythrocyte-binding antigen-175 [EBA175] [ 22 ], full-length P. falciparum reticulocyte-binding homologue protein 2 and 5 (PfRH2 [ 23 ] and PfRH5 [ 24 ])), and biomarkers of recent P. falciparum exposure [ 25 ] (gametocyte exported protein 18 [GEXP18], acyl CoA synthetase 5 [ACS5] ag3, early transcribed membrane protein 5 [ETRAMP5] ag1 and heat shock protein 40 [HSP40] ag1). Information about antigens, procedures for reconstitution of DBS and quality control, bead-based immunoassay, and data normalization are described in Additional File 1 : Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Antibody levels were higher among women from Ilha Josina (all antigens), HIV-infected (all antigens except ACS5), those residing in rural settings (DBL3-4, RII/F2-EBA175, PfRH2, PfRH5, GEXP18, ACS5, ETRAMP, HSP40), and multigravidae (DBL3-4, P1, MSP1 19 , RII/F2-EBA175, GEXP18 and ACS5; Fig. 3 and Additional File 1: Fig.…”

Section: Immunoglobulin G Levels Against P Falciparum Antigensmentioning

confidence: 99%

Gravidity and malaria trends interact to modify P. falciparum densities and detectability in pregnancy: a 3-year prospective multi-site observational study

Matambisso

Brokhattingen

Maculuve

et al. 2022

BMC Med

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Background Low-density Plasmodium falciparum infections prevail in low transmission settings, where immunity is expected to be minimal, suggesting an immune-independent effect on parasite densities. We aimed to describe parasite densities in pregnancy, and determine how gravidity and antibody-mediated immunity affect these, during a period of declining malaria transmission in southern Mozambique. Methods We documented P. falciparum infections at first antenatal care visits (n = 6471) between November 2016 and October 2019 in Ilha Josina (high-to-moderate transmission area), Manhiça (low transmission area), and Magude (pre-elimination area). Two-way interactions in mixed-effects regression models were used to assess gravidity-dependent differences in quantitative PCR-determined P. falciparum positivity rates (PfPRqPCR) and densities, in the relative proportion of detectable infections (pDi) with current diagnostic tests (≥ 100 parasites/μL) and in antimalarial antibodies. Results PfPRqPCR declined from 28 to 13% in Ilha Josina and from 5–7 to 2% in Magude and Manhiça. In primigravidae, pDi was highest in Ilha Josina at the first study year (p = 0.048), which declined with falling PfPRqPCR (relative change/year: 0.41, 95% CI [0.08; 0.73], p = 0.029), with no differences in antibody levels. Higher parasite densities in primigravidae from Ilha Josina during the first year were accompanied by a larger reduction of maternal hemoglobin levels (− 1.60, 95% CI [− 2.49; − 0.72; p < 0.001), than in Magude (− 0.76, 95% CI [− 1.51; − 0.01]; p = 0.047) and Manhiça (− 0.44, 95% CI [− 0.99; 0.10; p = 0.112). In contrast, multigravidae during the transmission peak in Ilha Josina carried the lowest pDi (p = 0.049). As PfPRqPCR declined, geometric mean of parasite densities increased (4.63, 95% CI [1.28; 16.82], p = 0.020), and antibody levels declined among secundigravidae from Ilha Josina. Conclusions The proportion of detectable and clinically relevant infections is the highest in primigravid women from high-to-moderate transmission settings and decreases with declining malaria. In contrast, the falling malaria trends are accompanied by increased parasite densities and reduced humoral immunity among secundigravidae. Factors other than acquired immunity thus emerge as potentially important for producing less detectable infections among primigravidae during marked declines in malaria transmission.

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“…Antibodies specific for Plasmodium spp. blood-stage antigens, in particular Pf VAR2CSA, are an attractive candidate for sero-surveillance of malaria in pregnancy as they have been demonstrated as a biomarker of recent exposure to malaria during pregnancy (systematically reviewed in [ 17 ]) and to monitor changes in malaria transmission over time [ 35 ]. However, the antibody to Pf VAR2CSA when used on its own was not the best marker of malaria infection in pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Quantification of the dynamics of antibody response to malaria to inform sero-surveillance in pregnant women

Dharmaratne

Dini

O’Flaherty

et al. 2022

Malar J

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Background Malaria remains a major public health threat and tools sensitive to detect infections in low malaria transmission areas are needed to progress elimination efforts. Pregnant women are particularly vulnerable to malaria infections. Throughout pregnancy they access routine antenatal care, presenting a unique sentinel population to apply novel sero-surveillance tools to measure malaria transmission. The aim of this study was to quantify the dynamic antibody responses to multiple antigens during pregnancy so as to identify a single or multiple antibody response of exposure to malaria in pregnancy. Methods This study involved a secondary analysis of antibody responses to six parasite antigens [five commonly studied merozoite antigens and the variant surface antigen 2-chondroitin sulphate A (VAR2CSA), a pregnancy-specific erythrocytic antigen] measured by enzyme-linked immunosorbent assay (ELISA) over the gestation period until delivery (median of 7 measurements/woman) in 250 pregnant women who attended antenatal clinics located at the Thai-Myanmar border. A multivariate mixture linear mixed model was used to cluster the pregnant women into groups that have similar longitudinal antibody responses to all six antigens over the gestational period using a Bayesian approach. The variable-specific entropy was calculated to identify the antibody responses that have the highest influence on the classification of the women into clusters, and subsequent agreement with grouping of women based on exposure to malaria during pregnancy. Results Of the 250 pregnant women, 135 had a Plasmodium infection detected by light microscopy during pregnancy (39% Plasmodium falciparum only, 33% Plasmodium vivax only and 28% mixed/other species), defined as cases. The antibody responses to all six antigens accurately identified the women who did not have a malaria infection detected during pregnancy (93%, 107/115 controls). Antibody responses to P. falciparum merozoite surface protein 3 (PfMSP3) and P. vivax apical membrane antigen 1 (PvAMA1) were the least dynamic. Antibody responses to the antigens P. falciparum apical membrane antigen 1 (PfAMA1) and PfVAR2CSA were able to identify the majority of the cases more accurately (63%, 85/135). Conclusion These findings suggest that the combination of antibodies, PfAMA1 and PfVAR2CSA, may be useful for sero-surveillance of malaria infections in pregnant women, particularly in low malaria transmission settings. Further investigation of other antibody markers is warranted considering these antibodies combined only detected 63% of the malaria infections during pregnancy.

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VAR2CSA Serology to Detect Plasmodium falciparum Transmission Patterns in Pregnancy

Cited by 12 publications

References 29 publications

Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria

Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria

Gravidity and malaria trends interact to modify P. falciparum densities and detectability in pregnancy: a 3-year prospective multi-site observational study

Quantification of the dynamics of antibody response to malaria to inform sero-surveillance in pregnant women

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