Prospects and Pitfalls of Pregnancy-Associated Malaria Vaccination Based on the Natural Immune Response to Plasmodium falciparum VAR2CSA-Expressing Parasites
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. 1. Introduction Over 50 million women who live in areas of high malaria transmission become pregnant every year, and thousands of these women die [1]. Women in their first and second pregnancies are at particular risk of infection with Plasmodium falciparum, which is a major risk factor for maternal and foetal mortality and is implicated in 75,000–200,000 infant deaths per annum [2, 3]. Selective accumulation of parasites in the placental space results in maternal anaemia [4–6] and infant low birth weight (LBW) [7–13] through preterm delivery (PTD) [12, 13] and intrauterine growth restriction (IUGR) [7, 10, 12, 13]. Malaria demands up to 5% of the gross domestic product in sub-Saharan Africa [14]. Pregnancy-associated malaria (PAM) infection is one example of a severe malaria syndrome, mediated by the surface expression of variant surface antigens (VSAs) of P. falciparum parasitised red blood cells (pRBC) that allow adherence to vascular endothelium. In non-pregnant individuals, VSAs adhere to the ubiquitous endothelial surface proteins intercellular adhesion molecule-1 (ICAM-1) and CD36 or to other pRBC or form rosettes around non-infected RBC. Under high transmission settings with favourable breeding sites for the vector Anopheles mosquito, adults acquire natural
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