Protection from placental malaria is thought to be mediated by anti-VAR2CSA antibodies that inhibit parasite adherence to placental chondroitin sulfate proteoglycans (CSPGs) in the placental syncytium. However, the epidemiological evidence for the protective effect of anti-VAR2CSA antibodies and its magnitude is unclear. We conducted a systematic review and meta-analysis to investigate the association between anti-VAR2CSA antibodies and placental malaria, low birthweight, and preterm birth, in order to identify suitable antigens for the development of serosurveillance tools and vaccines.
We searched six databases for population-based cross-sectional, case-control, and cohort studies published up to 17 April 2018 that examined associations between IgG antibody responses to pregnancy-specific P. falciparum isolates and/or recombinant VAR2CSA antigens and placental malaria, low birthweight, and/or preterm birth. Participants included pregnant women living in malaria endemic areas globally. Where possible, a pooled effect for each outcome was estimated using a random-effects meta-analysis model.
We identified 15 studies that met the inclusion and quality criteria, most of which were conducted in Africa. There was considerable heterogeneity observed in the direction of effect, study design, antigens examined, and antibody assays performed. Antibody responses to VAR2CSA DBL5 and ID1-ID2 domains, measured at delivery, were associated with increased odds of placental malaria in geographically diverse populations, suggesting these antigens may serve as biomarkers for placental infection.
Further prospective longitudinal cohort studies are required to demonstrate whether antibody responses to VAR2CSA protect against placental malaria and to identify antigens suitable for serosurveillance and vaccine development.