Effects of Sex, Parity, and Sequence Variation on Seroreactivity to Candidate Pregnancy Malaria Vaccine Antigens

Oleinikov, Andrew V.; Rossnagle, Eddie; Francis, Susan E.; Mutabingwa, Theonest K.; Fried, Michal; Duffy, Patrick E.

doi:10.1086/518513

Cited by 49 publications

(61 citation statements)

References 31 publications

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“…An important consideration is whether these antibodies are protective. The current thinking is that antibodies against VAR2CSA are acquired in a parity-dependent manner, and high levels of antibodies are associated with improved birth outcomes (46). We were unable to observe parity-dependent effects on anti-VAR2CSA IgG levels in our pregnant population given the small sample size of pregnant women with known parity.…”

Section: Discussionmentioning

confidence: 76%

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

et al. 2014

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iIn pregnancy, parity-dependent immunity is observed in response to placental infection with Plasmodium falciparum. Antibodies recognize the surface antigen, VAR2CSA, expressed on infected red blood cells and inhibit cytoadherence to the placental tissue. In most settings of malaria endemicity, antibodies against VAR2CSA are predominantly observed in multigravid women and infrequently in men, children, and nulligravid women. However, in Colombia, we detected antibodies against multiple constructs of VAR2CSA among men and children with acute P. falciparum and Plasmodium vivax infection. The majority of men and children (>60%) had high levels of IgGs against three recombinant domains of VAR2CSA: DBL5, DBL3X, and ID1-ID2. Surprisingly, these antibodies were observed only in pregnant women, men, and children exposed either to P. falciparum or to P. vivax. Moreover, the anti-VAR2CSA antibodies are of high avidity and efficiently inhibit adherence of infected red blood cells to chondroitin sulfate A in vitro, suggesting that they are specific and functional. These unexpected results suggest that there may be genotypic or phenotypic differences in the parasites of this region or in the host response to either P. falciparum or P. vivax infection outside pregnancy. These findings may hold significant clinical relevance to the pathophysiology and outcome of malaria infections in this region.

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Section: Discussionmentioning

confidence: 76%

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

et al. 2014

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“…Antibodies toward VAR2CSA are acquired in a parity-dependent manner in pregnant women exposed to P. falciparum infection (29). We therefore analyzed the impact of parity on the immune recognition of different 3D7-VAR2CSA constructs using plasma samples originating from either primigravid or multigravid women, regardless of P. falciparum infection ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Parity-Dependent Recognition of DBL1X-3X Suggests an Important Role of the VAR2CSA High-Affinity CSA-Binding Region in the Development of the Humoral Response against Placental Malaria

et al. 2015

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f Plasmodium falciparum multidomain protein VAR2CSA stands today as the leading vaccine candidate against pregnancy-associated malaria (PAM). Most of the studies aiming to decrypt how naturally acquired immunity develops have assessed the immune recognition of individual VAR2CSA Duffy-binding-like (DBL) domains, thus overlooking the presence of conformational epitopes resulting from the overall folding of the full-length protein. In order to characterize the development of humoral immunity toward VAR2CSA, we made use of a large cohort of 293 Senegalese pregnant women to assess the level of recognition by plasma IgG of the full-length VAR2CSA protein of the 3D7 parasite strain (3D7-VAR2CSA), the CSA-binding multidomains 3D7-DBL1X to -DBL3X (3D7-DBL1X-3X), and the CSA nonbinding multidomains 3D7-DBL4 to -DBL6 (3D7-DBL4-6), as well as individual 3D7-DBL domains. Our results revealed a parity-dependent recognition of the full-length 3D7-VAR2CSA and of the CSA-binding region, 3D7-DBL1X-3X. Indeed, multigravid women possess significantly higher levels of antibodies directed against these constructs than primigravidae. Our results suggest an important role of antibodies targeting the CSA-binding region in the development of immunity against PAM, therefore providing new insights on how natural protection might be acquired and further information for the design of VAR2CSA-based vaccines. E ach year, pregnancy-associated malaria (PAM) is responsible for the deaths of as many as 363,000 neonates and for at least 10,000 maternal deaths worldwide (1). The massive accumulation of Plasmodium falciparum-infected erythrocytes (IEs) to the syncytiotrophoblast layer composing the maternal face of the placenta limits maternal-fetal exchanges, leading to clinical complications for both mother and child (2). This phenomenon is mediated by the VAR2CSA protein, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesins, that is preferentially expressed by placental parasites (3-5) and binds to the placental chondroitin-4-sulfate A (CSA) (6). After one or two pregnancies, women acquire antibodies targeting VAR2CSA that inhibit IE sequestration and decrease the negative outcomes of PAM (7,8). In vitro assays have shown that antibodies from multigravid women are able to block the interactions between CSA and IEs originating from different parts of the world (9), showing the existence of a cross-reactive antibody response and suggesting that a relative conservation of important inhibitory epitopes within VAR2CSA proteins may exit.VAR2CSA is a 350-kDa transmembrane protein composed of six Duffy-binding-like (DBL) domains. Previous works have described the CSA-binding properties of single DBL domains (3, 10, 11). Insight derived from structural studies of DBL domains revealed the importance of the DBL3X domain in VAR2CSA CSA binding but also suggested a higher-order structure organization of VAR2CSA where the positioning of different surfaces involved in chondroitin sulfate proteoglycan (CSPG) binding forms a specific bin...

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“…Also, recombinant DBL3X may be folded in such a way that some critical epitopes present in recombinant DBL3X-S3 may be masked. Of interest, seroepidemiological studies of five of the six VAR2CSA DBL domains suggest that DBL3X and DBL5ε are more immunodominant than other domains (42,43,44). However, DBL2X has not been analyzed in previous seroepidemiological studies.…”

Section: Discussionmentioning

confidence: 99%

Identification of VAR2CSA Domain-Specific Inhibitory Antibodies of the Plasmodium falciparum Erythrocyte Membrane Protein 1 Using a Novel Flow Cytometry Assay

Obiakor¹,

Avril²,

MacDonald³

et al. 2013

Clin. Vaccine Immunol.

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Effects of Sex, Parity, and Sequence Variation on Seroreactivity to Candidate Pregnancy Malaria Vaccine Antigens

Abstract: Women acquire antibodies to VAR2CSA over successive pregnancies, but they lose reactivity to VAR1CSA. Serum reactivity to VAR2CSA is variant specific, and future studies should examine the degree to which functional antibodies, such as binding-inhibition antibodies, are variant specific.

Cited by 49 publications

References 31 publications

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

Parity-Dependent Recognition of DBL1X-3X Suggests an Important Role of the VAR2CSA High-Affinity CSA-Binding Region in the Development of the Humoral Response against Placental Malaria

Identification of VAR2CSA Domain-Specific Inhibitory Antibodies of the Plasmodium falciparum Erythrocyte Membrane Protein 1 Using a Novel Flow Cytometry Assay

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