A conformational epitope in placental malaria vaccine antigen VAR2CSA: What does it teach us?

Abstract

VAR2CSA is the Plasmodium falciparum variant surface antigen that mediates binding of infected erythrocytes to chondroitin sulfate A (CSA) and their sequestration in intervillous spaces of the placenta, leading to placental malaria (PM). Relatively high polymorphism in VAR2CSA sequences has hindered development of a vaccine that induces broadly neutralizing immunity. Recent research has highlighted that a broadly reactive human monoclonal antibody, called PAM1.4, binds to multiple conserved residues of different subfragments of VAR2CSA, forming a conformational epitope. In this short perspective, we describe evidence that residues located in the interdomain-1 fragment of VAR2CSA within the PAM1.4 binding epitope might be critical to broad reactivity of the antibody. Future investigation into broadly reactive anti-VAR2CSA antibodies may be important for the following: (1) identification of similar conformation epitopes targeted by broadly neutralizing antibodies; and (2) understanding different immune evasion mechanisms used by placenta-binding parasites through VAR2CSA polymorphism in critical epitopes.

Fig 1. PAM1.4-binding profile to genetically diverse VAR2CSA recombinants.

VAR2CSA protein sequence diversity of the 7 full-length VAR2CSA ectodomain has been analysed to highlight (A) sequence identity within the 7 phylogenetically distant alleles of VAR2CSA, reported in Renn and colleagues [12], by multiple alignment of NTS-DBL6 fragments (ranged from 2,640 to 2,723 amino acids) using BioEdit version 7.0.5.3 software. (B) The structure of VAR2CSA complex with PAM1.4 (PDB:7Z12) reported in Raghavan and colleagues [11] was used to map the PAMVAC (in blue) and PRIMVAC (in red) vaccine boundaries, while VH:VL chains of PAM1:4 are highlighted in orange and green. (C) The binding level of human monoclonal IgG PAM1.4 and (D) pooled purified IgG from MG to the 7 full-length VAR2CSA (Fv2) recombinants was measured by ELISA. OD units are reported. IgG, immunoglobulin G; MG, multigravidae; OD, optical density.