Acquisition of antibodies to variant antigens on the surface of Plasmodium falciparum-infected erythrocytes during pregnancy
Introduction
In Plasmodium falciparum endemic areas, previously immune women become more susceptible to malaria during their first pregnancy. The prevalence rates of peripheral and placental parasitemias, as well as their densities, are highest in primigravidae (Brabin, 1983, Steketee et al., 1988), decreasing after the second pregnancy. Pregnancy-associated malaria (PAM) is characterized by the accumulation of infected red blood cells (IRBC) in the placenta (Fried and Duffy, 1996). PAM is responsible for low birth weight, abortion and maternal mortality (Menendez et al., 2000). Chondroitin sulfate A (CSA) expressed on syncytiotrophoblast mediates the adherence of IRBC to placenta (Fried and Duffy, 1996) in association with the expression of a distinct variant surface antigen (VSA) on the membrane of IRBC. The major falciparum antigen involved is the variant P. falciparum erythrocyte membrane protein-1 (PfEMP1), each variant mediating adhesion of IRBC to a specific host molecule (Buffet et al., 1999). PAM is caused by P. falciparum which express peculiar VSAs (VSACSA) that allow the parasite to bind CSA and sequester in the placenta (Rogerson et al., 1995). Conversely to the VSA expressed by parasites infecting non-pregnant hosts, these VSACSA are reasonably conserved antigens (Khattab et al., 2003). In areas of intense malaria transmission, antibody levels to VSACSA increase with gravidity, block the adhesion of IRBC to CSA (Fried et al., 1998, Gysin et al., 1999, Maubert et al., 1999, O’Neil-Dunne et al., 2001), and protect against low birth weight and maternal anemia (Staalsoe et al., 2004). A placental infection during first pregnancy was suggested to induce a substantial antibody response to CSA-binding IRBC (Beeson et al., 2004), raising hope for a potential VSA-based vaccine against PAM. Studies reported that anti-VSACSA-specific antibodies are not acquired earlier than halfway through the first pregnancy (O’Neil-Dunne et al., 2001, Staalsoe et al., 2001). In the present work, we aimed to investigate the relationships between parity, placental infection and presence of anti-VSACSA antibody. In addition, we assessed the relation between the occurrence of P. falciparum infections during pregnancy and the development of an anti-VSACSA antibody response against three different placental isolates.
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Study population
We studied 306 pregnant women in Thiadiaye, Senegal, where the rainy season lasts from July to October (500 mm of annual rains). Malaria transmission is stable and seasonal, occurring following the first rains from mid-September to mid-November. The estimated average number of infective bites is 10 per person and per year (Robert et al., 1998). The Ethical Committee, Ministry of Health, Senegal provided ethical approval for this research. All participants gave informed consent.
Pregnant women
Results
Among the 306 women enrolled, 12 were lost to follow-up, and at least one serum sample was lacking for 29, therefore 265 women were included in the analysis. Mean age of the women was 26 years (median 25 and interquartile range [20–30]). Sixty-two women were primigravidae, 50 secundigravidae and 153 multigravidae. Mean gestational age at enrollment was 18.5 weeks (median = 20 and interquartile range [16–22]). One hundred and eighteen women (44.5%) presented with at least one P. falciparum
Discussion
In areas of intense P. falciparum transmission, pregnant women develop protective immunity to PAM over successive infected pregnancies, and only primigravidae and secundigravidae present higher placental infection prevalence rates (Steketee et al., 1988). In Senegal, where malaria transmission is low and highly seasonal, placental infection prevalence rates decrease after the first pregnancy and remain stable thereafter. The relatively high overall placental infection rate (16.6%) in this area
Acknowledgements
The work received financial support from the European Commission (QLK2-CT-2001-01302) and the French Ministry of Research (ACI Pal+/2001). The support of the maternity staff of Guediawaye and Thiadiaye health centres in sample collection is acknowledged. We are grateful to the mothers who participated in the study. We acknowledge the IRD research unit in Senegal, especially Mamadou Ngom, for practical support.
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Designing a VAR2CSA-based vaccine to prevent placental malaria
2015, VaccineCitation Excerpt :Low antibody reactivity with the IE surface was associated with lower hemoglobin level and reduced birthweight [9]. Antibodies that react to the IE surface by flow, or that opsonize or agglutinate CSA-binding IE, also develop in naturally exposed women [9,27–38], although the evidence base is smaller that these antibodies might be associated with clinical outcomes. Because VAR2CSA is the leading vaccine target, several studies have compared VAR2CSA domains for reactivity to sera of primigravid and multigravid women in order to support vaccine design (Table 1).
Malaria, primigravidae, and antibodies: Knowledge gained and future perspectives
2014, Trends in ParasitologyCitation Excerpt :In 2006 a panel of placental isolates and CSA-binding parasite lines was used to demonstrate that MG not only had higher antibody levels, but also a greater breadth of recognition of CSA-binding isolates, than did PG [42]. A single or a very limited number of P. falciparum infections were shown to be sufficient to induce an anti-VSA antibody response in Senegalese PG, but these initial responses did not appear to confer protection against PM, again emphasising the role of these antibodies as markers of exposure [43]. Also in 2006, levels of IgG against Duffy binding-like (DBL) domains of VAR2CSA, termed DBL1X, DBL5ɛ, and DBL6ɛ, were higher in PG than in men or NG, but were lower than those in MG.
Malaria during pregnancy
2017, Cold Spring Harbor Perspectives in Medicine