Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope.

Catherine J Mitran,Lauren M Higa,Michael F Good,Stephanie K Yanow

doi:10.3390/vaccines8030392

Catherine J Mitran, Lauren M Higa + Show 2 more

Open Access

https://doi.org/10.3390/vaccines8030392

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Journal: Vaccines	Publication Date: Jul 18, 2020
Citations: 7	License type: CC BY 4.0

Affiliation: University of Alberta, Griffith University

Abstract

In pregnant women, Plasmodium falciparum-infected red blood cells adhere to the placenta via the parasite protein VAR2CSA. Two vaccine candidates based on VAR2CSA are currently in clinical trials; however, these candidates failed to elicit strain-transcending antibody responses. We previously showed that a cross-reactive monoclonal antibody (3D10) raised against the P. vivax antigen PvDBP targets epitopes in VAR2CSA. We now aim to design a peptide vaccine against VAR2CSA based on the epitope that generated 3D10. We mapped the epitope to subdomain 1 (SD1) of PvDBP and identified a peptide that contained the minimal sequence. However, this peptide did not elicit cross-reactive VAR2CSA antibodies in mice. When tested against a broader, overlapping peptide array spanning SD1, 3D10 in fact recognized a discontinuous epitope consisting of three segments of SD1. These findings presented the challenge to generate this larger structural epitope as a synthetic peptide since it is stabilized by two pairs of disulfide bonds. We overcame this using a synthetic scaffold to conformationally constrain the SD1 peptide and coupled it to keyhole limpet hemocyanin (KLH). The SD1-KLH conjugate elicited antibodies in mice that cross-reacted with VAR2CSA. This strategy successfully recapitulated a discontinuous epitope with a synthetic peptide and represents the first heterologous vaccine candidate against VAR2CSA.

Highlights

Pregnancy-associated malaria caused by infection with the parasite Plasmodium falciparum can result in preterm birth, low birth weight babies, spontaneous abortion, and infant and maternal death [1]
In order to identify the minimal epitope for 3D10 recognition, we designed a number of synthetic peptides spanning the subdomain 1 (SD1): SD1 region of DBPII (Figure 1)
We identified a conformationally constrained synthetic peptide exists between DBPII and VAR2CSA

Summary

Introduction

Pregnancy-associated malaria caused by infection with the parasite Plasmodium falciparum can result in preterm birth, low birth weight babies, spontaneous abortion, and infant and maternal death [1]. The leading vaccine candidates are based on VAR2CSA, a P. falciparum protein that mediates sequestration of infected red blood cells to the placenta [2,3,4,5,6,7]. While these vaccines show promise by eliciting strong antibodies to the homologous VAR2CSA allele, they failed to elicit broadly neutralizing antibodies against heterogeneous parasite strains due to extensive natural polymorphisms within VAR2CSA [6,7,8]. The source of these antibodies is an epitope shared between the Duffy binding-like (DBL)

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