Invited review
Pregnancy-associated malaria: Parasite binding, natural immunity and vaccine development

https://doi.org/10.1016/j.ijpara.2006.11.011Get rights and content

Abstract

Humans living in areas of high malaria transmission gradually acquire, during the early years of life, protective clinical immunity to Plasmodium falciparum, limiting serious complications of malaria to young children. However, pregnant women become more susceptible to severe P. falciparum infections during their first pregnancy. Pregnancy associated malaria is coupled with massive accumulation of parasitised erythrocytes and monocytes in the placental intervillous blood spaces, contributing to disease and death in pregnant women and developing infants. Indirect evidence suggests that prevention may be possible by vaccinating women of childbearing age before their first pregnancy. This review aims to introduce the reader to the implications of malaria infection during pregnancy and to analyse recent findings towards the identification and characterisation of parasite encoded erythrocyte surface proteins expressed in malaria-infected pregnant women that are likely targets of protective immunity and have potential for vaccine development.

Introduction

The clinical impact of pregnancy-associated malaria (PAM) was first described 70 years ago and since then has been the subject of more than 2000 scientific papers (for review, see Brabin et al., 2004). Adverse outcomes include low birth weight babies, fetal loss, increased perinatal and maternal mortality, maternal anemia and the risk of hypertension in first-time pregnant mothers (Muehlenbachs et al., 2006). However, until recently it was not clear why high parasitemia occurred in pregnant women who otherwise possess significant clinical immunity to malaria. The basis for the accumulation of parasitised erythrocytes (PEs) in the placenta was unknown until it was shown that PEs from placenta bind to chondroitin sulfate A (CSA) and not to CD36, a common receptor for PE sequestration in the microvasculature (Fried and Duffy, 1996). This was the first direct evidence that a switch in parasite adhesion phenotype could regulate PE sequestration at different microvascular sites within the body and suggested that the placenta supports the clonal expansion of a unique subset of variants to which immunity has not yet developed.

Significantly, after one or two pregnancies transcendent antibodies that recognise placental PEs from different geographic regions develop and correlate with protection from malaria (Duffy and Fried, 2003, Fried et al., 1998, Staalsoe et al., 2004). Fried et al. (1998) were the first to show that antibodies against CSA-binding parasites are associated with maternal malaria resistance after multiple pregnancies and also block CSA-binding of placental isolates from different parts of the world, demonstrating the concept of a transcending immune response to the Plasmodium falciparum CSA ligand. These findings suggest that the surface molecule(s) expressed by placental variants have conserved antigenic determinants and have spurred efforts to characterise these protective antibodies and to induce them by vaccination. How and when natural PAM immunity develops is incompletely understood but will be important for designing a pregnancy malaria vaccine.

Section snippets

Pregnancy-associated malaria and natural protective immunity

Women develop increasing resistance to PAM infections over successive pregnancies (Brabin et al., 2004). This pattern of parity-specific resistance has been associated with the acquisition of antibodies to the surface of placental PEs (Beeson et al., 1999, Fried et al., 1998, Maubert et al., 1999, Ricke et al., 2000). Early in first pregnancies, women generally lack antibodies that react with the surface of placental binding PEs, which suggests these express novel surface variants. However, by

Parasite ligands mediating adhesion to CSA

The observation that maternal antibodies are broadly reactive to geographically diverse placental isolates underpins PAM vaccine efforts but also presents one of the central paradoxes for PAM immunity. Although this finding implies that placental isolates have shared epitopes, the only parasite antigens known to be at the PE surface at the time this observation was made were members of a highly diverse P. falciparum erythrocyte membrane protein 1 (PfEMP1) family encoded by var genes (Baruch et

Var1CSA and varCS2: two puzzling CSA binding var genes

In 1999, two var genes (FCR3varCSA and varCS2) were identified as being implicated in the CSA adhesion phenotype of the IT/FCR3 strain by two different groups (Buffet et al., 1999, Reeder et al., 1999). FCR3varCSA, also renamed var1CSA, encodes for a PfEMP1 protein that possesses eight receptor-like domains (seven DBL domains and one CIDR) (Fig. 2), whereas the varCS2 gene encodes for five domains (three DBL domains and two CIDR). By expressing recombinant proteins, it was shown that a DBLγ

Var2CSA: a predominant var gene expressed in placental isolates

At the time that researchers were trying to identify the var gene(s) involved in CSA adhesion, RT-PCR experiments were designed using degenerate primers based on the known DBL-α sequences present in the database (Peterson et al., 1995, Taylor et al., 2000). These primers were thought to cover most var genes, but with the release of the P. falciparum isolate 3D7 genome sequence, atypical var genes without DBL-α, or with highly divergent DBL-α, were identified. New primers specific for each var

Antigenic polymorphism in var2CSA

A central issue in pregnancy malaria vaccine development is to determine the specificity and antigenic diversity of epitopes targeted by protective maternal antibodies. While maternal antibodies are broadly reactive to placental isolates, it is not clear if placental isolates have highly conserved epitopes or if this cross-reactivity reflects different antibody specificities in the pool of antiserum. Indeed, recent serological comparisons suggest there is considerable antigenic polymorphism in

Intervention strategies against the CSA binding ligands

A promising avenue for new intervention strategies against PAM is to provide young women with the necessary immunity that would protect first time pregnant mothers and their fetuses against severe complications of placental infections. Either therapeutic antibodies or vaccination using recombinant var2CSA proteins are being considered. Before therapeutic antibodies can be provided to pregnant women, the potential risks to the fetus and mother, dosing schedule and approaches for monitoring the

Other receptors involved in PAM

While CSA is considered the major receptor for placental sequestration, the question arises whether other host receptors are responsible for PE binding to the syncytiotrophoblast layer or within the intervillous blood spaces where the majority of infected erythrocytes accumulate (Muthusamy et al., 2004). Two host receptors other than CSA have been postulated to play a role in placental sequestration: hyaluronic acid (HA) (Beeson et al., 2000) and neonatal Fc receptors via non-immune

Conclusion

Placental malaria is a classic example of malaria research that demonstrates the extraordinary benefit of bench work combined with field studies. The initial observation that laboratory parasites can bind to CSA helped frame the unique character of parasites isolated from the placenta. This observation has opened new avenues in the field of PAM and work on laboratory strains has been valuable in identifying the var gene that plays a key role in PAM. Conceptually, we are now moving closer to the

Acknowledgements

The authors are supported by a grant from the Bill & Melinda Gates Foundation (Grant No. 29202) as part of the Pregnancy Malaria vaccine consortium; A.S. and J.G. are supported by the BIOMALPAR program (LSHP-CT-2004-503578), an FP6-funded network of excellence; B.G. and J.G. are supported by a grant from the European Malaria Vaccine Initiative (Grant No. 01/2005); A.S. and J.G. are supported by a grant from the “Fonds dédié: Combattre les Maladies parasitaires” Sanofi Aventis – Ministère de la

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    These authors contributed equally to the work.

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