VAR2CSA binding phenotype has ancient origin and arose before Plasmodium falciparum crossed to humans: implications in placental malaria vaccine design

Sébastien Dechavanne,Marion Avril,Anand Srivastava,Benoît Gamain,Joseph D Smith,Arnaud Chêne,Stéphane Gangnard

doi:10.1038/s41598-019-53334-8

Abstract

VAR2CSA is a leading candidate for developing a placental malaria (PM) vaccine that would protect pregnant women living in malaria endemic areas against placental infections and improve birth outcomes. Two VAR2CSA-based PM vaccines are currently under clinical trials, but it is still unclear if the use of a single VAR2CSA variant will be sufficient to induce a broad enough humoral response in humans to cross-react with genetically diverse parasite populations. Additional immuno-focusing vaccine strategies may therefore be required to identify functionally conserved antibody epitopes in VAR2CSA. We explored the possibility that conserved epitopes could exist between VAR2CSA from the chimpanzee parasite Plasmodium reichenowi and Plasmodium falciparum sequences. Making use of VAR2CSA recombinant proteins originating from both species, we showed that VAR2CSA from P. reichenowi (Pr-VAR2CSA) binds to the placental receptor CSA with high specificity and affinity. Antibodies raised against Pr-VAR2CSA were able to recognize native VAR2CSA from different P. falciparum genotypes and to inhibit the interaction between CSA and P. falciparum-infected erythrocytes expressing different VAR2CSA variants. Our work revealed the existence of cross-species inhibitory epitopes in VAR2CSA and calls for pre-clinical studies assessing the efficacy of novel VAR2CSA-based cross-species boosting regimens.

Highlights

Placental malaria (PM) is a serious complication of malaria infection associated with accumulation of Plasmodium falciparum infected erythrocytes (IEs) in the placental intervillous space[1,2,3], leading to adverse health consequences for both mother and child[4]
As compared to P. falciparum, the extracellular part of the protein is limited to the NTS-DBL1x-interdomain 1 (ID1)-DBL2x-truncated interdomain 2 (ID2) region (Fig. 1a)
Since the chondroitin sulphate A (CSA)-binding region of P. falciparum VAR2CSA resides within the ID1-DBL2x-ID2a region of the protein[27], we hypothesized that P. reichenowi VAR2CSA could harbour functional determinants allowing interaction with glycosaminoglycans

Summary

Introduction

Placental malaria (PM) is a serious complication of malaria infection associated with accumulation of Plasmodium falciparum infected erythrocytes (IEs) in the placental intervillous space[1,2,3], leading to adverse health consequences for both mother and child[4]. VAR2CSA is a large multidomain protein consisting of six Duffy-binding like (DBL) domains (three DBLx, followed by three DBLε). It contains a CIDRPAM domain between the DBL2x and DBL3x domains, in a region that is referred to as interdomain 2 (ID2). Little is known about the encoded cytoadhesive properties of the var-like genes in most Laverania parasites, analysis of CIDRα0 and CIDRα1 recombinant domains from P. reichenowi has provided evidence that the CD36 and EPCR adhesion traits arose in an ancestral species[24] prior to chimpanzee and human speciation. We provide evidence that Pr-VAR2CSA binds to CSA with similar affinity and specificity as VAR2CSA from P. falciparum (Pf-VAR2CSA), and that it has the capability to elicit cross-inhibitory antibodies against different CSA-binding P. falciparum parasite lines

Methods

Results

Conclusion