Trends in Parasitology
Volume 30, Issue 2, February 2014, Pages 85-94
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Review
Malaria, primigravidae, and antibodies: knowledge gained and future perspectives

https://doi.org/10.1016/j.pt.2013.12.007Get rights and content

Highlights

  • Primigravidae develop antibodies to P. falciparum that adheres to the placenta.

  • P. falciparum parasites that adhere to the placenta express VAR2CSA.

  • Antibodies to VAR2CSA correlate with gestational P. falciparum infection.

  • We propose serology and primigravidae as sentinels for malaria transmission.

Pregnant women have an increased risk of malaria infection, independent of previously acquired immunity. Women in their first pregnancy and children under the age of five are the primary victims of malaria worldwide. Pregnant women develop antibodies against placenta-adhesive parasites in a parity-dependent manner. Various efforts to understand the targets, quality, and quantity of this antibody response could aid the design of an effective vaccine against placental malaria. This review focuses on the research that has led to the current understanding of the antibody response that primigravidae (PG) acquire to Plasmodium falciparum malaria and draws from this knowledge to suggest serology and PG as sentinels for malaria transmission.

Section snippets

PG and serology: why look at it?

The study of malaria in pregnancy was, until the beginning of the 1980s and much throughout the following 15 years, based on observations that could not easily be explained. Pregnant women were known to be more susceptible to malaria than their non-pregnant counterparts 1, 2, 3; PG (see Glossary) were the most affected, suffering from severe anaemia and delivering low birth-weight (LBW) babies more frequently than multigravidae (MG) 1, 2, 3. In the 1960s and early 1970s, studies showed that

1980 to 1994: paradigms before chondroitin sulfate A (CSA)

Although the susceptibility of PG to the risks of malaria during pregnancy was well known, understanding why remained elusive into the late 1970s. In 1980 a longitudinal study on the acquisition of antimalarial antibodies during pregnancy showed that antibodies to P. falciparum, measured by an immunofluorescence assay (IFA), declined in the third trimester, although the study failed to identify PG as a separate group deserving special attention [7]. By contrast, levels of total IgG, IgM, IgA,

1995 to 2002: antibodies rise to fame, and parity-dependency is explained

As we have seen, subsequent to 1995, the prevailing idea in the field was that antibodies to malarial antigens during pregnancy did not explain the observed parity-dependent susceptibility to P. falciparum; instead, lower cellular immune responses in PG were thought to be responsible for that susceptibility as shown in three studies that addressed this topic in 1995–1997 17, 18, 19. In the first of these studies, the proliferative responses of peripheral mononuclear cells to malarial antigen in

2003 to 2006: antibodies protect and VAR2CSA debuts

As we have seen so far, although antibodies towards placental-type parasites seemed to protect women from high parasitaemias, they did not appear to induce clinical protection. That would soon change when in 2003 and 2004, the first reports describing associations between pregnancy-specific malaria antibodies and protection from adverse pregnancy outcomes were published. In a seminal paper from 2003, levels of adhesion-blocking antibodies in sera from secundigravidae, but not PG or MG,

2007 to 2010: antibodies team up with phagocytosis

In 2007 PG were shown to have lower reactivity to several domains of VAR2CSA, expressed as recombinant proteins, than MG [46], and these PG generally lacked antibodies that promoted the phagocytosis of placental-type parasites [47]. HIV had no effect on the levels of those antibodies [47]. In 2008, the levels of IgG3 which recognised the VAR2CSA domain DBL5ɛ were reported to be higher in PG without PM, suggesting that these antibodies may be important for protection [48], whereas in 2009 a

2010 to 2013: a focus on longitudinal studies and reinforcing old concepts

The past few years of research into the antibody responses in PG have seen some old concepts and ideas confirmed and given new strength, while highlighting the importance of longitudinal studies. When looking at the effect of both IPTp and use of bed nets on antibodies towards CSA-binding parasites, a greater decline was observed in antibodies towards CSA-binding parasites in PG than MG [54]. An evaluation of the levels of antibodies towards several P. falciparum parasites (both laboratory

A summary of 30 years of studies

As we have seen, over the past 30 years the relationship between malaria in pregnancy, PG, and antibodies has become much clearer (Table 2). From an early dismissal of antibodies as inconsequential to the realization that they are indeed important and can act on several different levels, not only as markers of malaria in pregnancy but also as effectors against it, the field has progressed substantially. PG, the group at most risk of suffering adverse outcomes, were not always the focus of these

PG as sentinels for malaria transmission?

Given what we now know about PG and antibodies to P. falciparum antigens during pregnancy (Table 2), could PG and their antibody responses be used as sentinels for malaria transmission? Considering this possibility raises a few questions. First, in general, does serology reflect malaria transmission within a given population? Several reports suggest that community-based seroconversion rates to malaria antigens are valuable tools for estimating malaria transmission, provided that the appropriate

Concluding remarks and future perspectives

Clearly, the study of PG and serology does not and should not finish here. The impact of IPTp on the acquisition of immunity in PG requires further study, particularly to evaluate the impact that it might have on subsequent pregnancies. The studies that are available so far, concerning PG, have overlooked the role played by local patterns of drug resistance, and lack consistency in approach, methods, and/or conclusions 37, 50, 51, 54.

Gaining a better understanding of the cell-mediated immunity

Glossary

Agglutinating antibodies
cause parasites to clump together when bound to an antigen on the parasite surface; potentially important as part of the immune response needed to control parasite numbers. Can in theory by any Ig isotype.
Antenatal clinic (ANC)
healthcare facility where pregnant women receive attention during their pregnancy. Routine exams performed will depend on the local setting and conditions.
Anti-adhesion antibodies
prevent parasite adhesion to receptors when bound to the surface of

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      However, the longevity of antibody responses against VAR2CSA and the effect of var2csa genetic diversity needs to be evaluated to determine the utility of such a serological approach. Although further validation is needed, the use of pregnant women as a sentinel group for malaria transmission, and the use of antibodies against VAR2CSA as markers of cumulative exposure to P falciparum during pregnancy,147 might be a feasible alternative to the generation of sensitive metrics of malaria transmission intensity for the elimination of malaria.137 The global burden of malaria in pregnancy is substantial.

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    *

    Current address: Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.

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