Abstract
BackgroundIn endemic areas, pregnant women are highly susceptible to Plasmodium falciparum malaria characterized by the accumulation of parasitized red blood cells (pRBC) in the placenta. In subsequent pregnancies, women develop protective immunity to pregnancy-associated malaria and this has been hypothesized to be due to the acquisition of antibodies to the parasite variant surface antigen VAR2CSA. In this systematic review we provide the first synthesis of the association between antibodies to pregnancy-specific P. falciparum antigens and pregnancy and birth outcomes.MethodsWe conducted a systematic review and meta-analysis of population-based studies (published up to 07 June 2019) of pregnant women living in P. falciparum endemic areas that examined antibody responses to pregnancy-specific P. falciparum antigens and outcomes including placental malaria, low birthweight, preterm birth, peripheral parasitaemia, maternal anaemia, and severe malaria.ResultsWe searched 6 databases and identified 33 studies (30 from Africa) that met predetermined inclusion and quality criteria: 16 studies contributed estimates in a format enabling inclusion in meta-analysis and 17 were included in narrative form only. Estimates were mostly from cross-sectional data (10 studies) and were heterogeneous in terms of magnitude and direction of effect. Included studies varied in terms of antigens tested, methodology used to measure antibody responses, and epidemiological setting. Antibody responses to pregnancy-specific pRBC and VAR2CSA antigens, measured at delivery, were associated with placental malaria (9 studies) and may therefore represent markers of infection, rather than correlates of protection. Antibody responses to pregnancy-specific pRBC, but not recombinant VAR2CSA antigens, were associated with trends towards protection from low birthweight (5 studies).ConclusionsWhilst antibody responses to several antigens were positively associated with the presence of placental and peripheral infections, this review did not identify evidence that any specific antibody response is associated with protection from pregnancy-associated malaria across multiple populations. Further prospective cohort studies using standardized laboratory methods to examine responses to a broad range of antigens in different epidemiological settings and throughout the gestational period, will be necessary to identify and prioritize pregnancy-specific P. falciparum antigens to advance the development of vaccines and serosurveillance tools targeting pregnant women.
Highlights
In endemic areas, pregnant women are highly susceptible to Plasmodium falciparum malaria characterized by the accumulation of parasitized red blood cells in the placenta
Search methods for identification of studies PubMed, Web of Science, Scopus, African Index Medicus, LILACS (Latin American and Caribbean Health Sciences Literature), and the Malaria in Pregnancy Consortium databases were searched for studies published in all years up to and including 07 June 2019 that examined the association of antibody responses to pregnancy-specific P. falciparum antigens and pregnancy and birth outcomes
A total of 33 studies were included in the systematic review: studies contributed estimates in a format enabling inclusion in meta-analysis [35, 42, 43, 51,52,53,54,55,56,57,58,59,60,61,62,63] (Table 1) and studies are included in narrative terms only because data were not available in the required format [27, 34, 38, 39, 64,65,66,67,68,69,70,71,72,73,74,75,76] (Table 2)
Summary
Pregnant women are highly susceptible to Plasmodium falciparum malaria characterized by the accumulation of parasitized red blood cells (pRBC) in the placenta. Parasites taken from infected placentas display preferential binding to the glycosaminoglycan chondroitin sulfate A (CSA) [15], present on the surface of placental syncytiotrophoblasts and intervillous spaces [15,16,17]. This binding phenotype is rarely observed in parasites taken from non-pregnant individuals [15, 18,19,20,21], which are more likely to bind to receptors CD36 and ICAM-1 in the vascular endothelium. Two vaccine candidates based on the N-terminal CSA-binding region of VAR2CSA [28] have entered early-stage clinical trials: PAMVAC is comprised of domains ID1-DBL2X-ID2a from the P. falciparum strain FCR3 [31, 32] and PRIMVAC is comprised of domains DBL1X–DBL2X from P.f. 3D7 [33]
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