Prospects and Pitfalls of Pregnancy-Associated Malaria Vaccination Based on the Natural Immune Response to Plasmodium falciparum VAR2CSA-Expressing Parasites

Abstract

Pregnancy-associated malaria, a manifestation of severe malaria, is the cause of up to 200,000 infant deaths a year, through the effects of placental insufficiency leading to growth restriction and preterm delivery. Development of a vaccine is one strategy for control. Plasmodium falciparum-infected red blood cells accumulate in the placenta through specific binding of pregnancy-associated parasite variants that express the VAR2CSA antigen to chondroitin sulphate A on the surface of syncytiotrophoblast cells. Parasite accumulation, accompanied by an inflammatory infiltrate, disrupts the cytokine balance of pregnancy with the potential to cause placental damage and compromise foetal growth. Multigravid women develop immunity towards VAR2CSA-expressing parasites in a gravidity-dependent manner which prevents unfavourable pregnancy outcomes. Although current vaccine design, targeting VAR2CSA antigens, has succeeded in inducing antibodies artificially, this candidate may not provide protection during the first trimester and may only protect those women living in areas endemic for malaria. It is concluded that while insufficient information about placental-parasite interactions is presently available to produce an effective vaccine, incremental progress is being made towards achieving this goal.

Figure 1

Interactions between immune cells and chemokines in placental malaria. References are found within the text. I-309 = CC/β chemokine, MCP-1: monocyte chemoattractant protein 1, MIP-1α/β: macrophage-inflammatory protein 1α/β, IL-8: interleukin 8—member of the CXC/α chemokine group.

Figure 2

Summary of immune interactions and outcomes in placental malaria. The box shows the interactions that are thought to be protective in multigravid women.

Figure 3

The duffy binding-like domains of the VAR2CSA molecule. Between each DBL region is an interdomain region that appears to be important for both binding properties and antibody induction. Each region has a differing degree of affinity for the CSA molecule on the placenta and individually the domains do not appear to display as strong binding ability as the whole VAR2CSA molecule. Recent evidence suggests that the first four domains are the most important for forming a quaternary structure that forms a complex binding site [228].