Abstract
BackgroundMalaria in pregnancy is a major cause of poor maternal and infant health, and is associated with the sequestration of P. falciparum-infected erythrocytes (IE) in the placenta. The leading vaccine candidate for pregnancy malaria, VAR2CSA, has been shown to induce antibodies that inhibit IE adhesion to the placental receptor chondroitin sulfate A (CSA), potentially preventing placental infection. However, the ability of vaccination-induced antibodies to promote opsonic phagocytosis is not well defined, but likely to be an important component of protective immunity.MethodsWe investigated the use of an opsonic phagocytosis assay to evaluate antibodies induced by pregnancy malaria vaccine candidate antigens based on VAR2CSA. Opsonic phagocytosis was measured by flow cytometry and visualized by electron microscopy. We measured vaccine-induced antibody reactivity to placental type IEs from different geographical origins, and the functional ability of antibodies raised in immunized rabbits to induce phagocytosis by a human monocyte cell line.ResultsImmunization-induced antibodies showed a mixture of strain-specific and cross-reactive antibody recognition of different placental-binding parasite lines. Antibodies generated against the DBL5 and DBL3 domains of VAR2CSA effectively promoted the opsonic phagocytosis of IEs by human monocytes; however, these functional antibodies were largely allele-specific and not cross-reactive. This has significant implications for the development of vaccines aiming to achieve a broad coverage against diverse parasite strains. Using competition ELISAs, we found that acquired human antibodies among pregnant women targeted both cross-reactive and allele-specific epitopes, consistent with what we observed with vaccine-induced antibodies.ConclusionsVaccines based on domains of VAR2CSA induced opsonic phagocytosis of IEs in a strain-specific manner. Assays measuring this phagocytic activity have the potential to aid the development and evaluation of vaccines against malaria in pregnancy.
Highlights
Malaria in pregnancy is a major cause of poor maternal and infant health, and is associated with the sequestration of P. falciparum-infected erythrocytes (IE) in the placenta
Study design To study the properties of vaccine-induced antibodies against pregnancy malaria, we measured the opsonic phagocytosis-inducing potential of antibodies to Duffy binding-like domain 5 (DBL5) and DBL3 raised through immunization of rabbits, which is a widely used pre-clinical model for malaria vaccine development
IgG from rabbits immunized with different DBL5 alleles (IT4, 7G8 and 3D7) showed varied reactivity to native VAR2CSA expressed on the surface of IEs of different chondroitin sulfate A (CSA)-binding parasite lines when measured by flow cytometry (Fig. 1a), as reported previously [22]
Summary
Malaria in pregnancy is a major cause of poor maternal and infant health, and is associated with the sequestration of P. falciparum-infected erythrocytes (IE) in the placenta. The leading vaccine candidate for pregnancy malaria, VAR2CSA, has been shown to induce antibodies that inhibit IE adhesion to the placental receptor chondroitin sulfate A (CSA), potentially preventing placental infection. Plasmodium falciparum-infected erythrocytes (IEs) sequester in the placenta via adhesion to chondroitin sulphate A (CSA) [3]. This interaction is mediated by a specific variant of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family known as VAR2CSA, and possibly other interactions [4]. Acquired antibodies directed against VAR2CSA are associated with the inhibition of CSA-binding by IEs [9, 10], reduced placental malaria [11] and improved pregnancy outcomes [12]. Funding has recently been secured for pre-clinical development and phase I trials of VAR2CSA-based vaccines
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