TY - JOUR

T1 - Mosaic and cocktail capsid-virus-like particle vaccines for induction of antibodies against the EPCR-binding CIDRα1 domain of PfEMP1

AU - Riedmiller, Ilary

AU - Fougeroux, Cyrielle

AU - Jensen, Rasmus W

AU - Kana, Ikhlaq H

AU - Sander, Adam F

AU - Theander, Thor G

AU - Lavstsen, Thomas

AU - Turner, Louise

N1 - Copyright: © 2024 Riedmiller et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2024

Y1 - 2024

N2 - The sequestration of Plasmodium falciparum-infected erythrocytes to the host endothelium is central to the pathogenesis of malaria. The sequestration is mediated by the parasite´s diverse Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants, which bind select human receptors on the endothelium. Severe malaria is associated with PfEMP1 binding human endothelial protein C receptor (EPCR) via their CIDRα1 domains. Antibodies binding and inhibiting across the sequence diverse CIDRα1 domains are likely important in acquired immunity against severe malaria. In this study, we explored if immunization with AP205 bacteriophage capsid-virus-like particles (cVLPs) presenting a mosaic of diverse CIDRα1 protein variants would stimulate broadly reactive and inhibitory antibody responses in mice. Three different mosaic cVLP vaccines each composed of five CIDRα1 protein variants with varying degrees of sequence conservation of residues at and near the EPCR binding site, were tested. All mosaic cVLP vaccines induced functional antibodies comparable to those induced by matched cocktails of cVLPs decorated with the single CIDRα1 variant. No broadly reactive responses were observed. However, the vaccines did induce some cross-reactivity and inhibition within the CIDRα1 subclasses included in the vaccines, demonstrating potential use of the cVLP vaccine platform for the design of multivalent vaccines.

AB - The sequestration of Plasmodium falciparum-infected erythrocytes to the host endothelium is central to the pathogenesis of malaria. The sequestration is mediated by the parasite´s diverse Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants, which bind select human receptors on the endothelium. Severe malaria is associated with PfEMP1 binding human endothelial protein C receptor (EPCR) via their CIDRα1 domains. Antibodies binding and inhibiting across the sequence diverse CIDRα1 domains are likely important in acquired immunity against severe malaria. In this study, we explored if immunization with AP205 bacteriophage capsid-virus-like particles (cVLPs) presenting a mosaic of diverse CIDRα1 protein variants would stimulate broadly reactive and inhibitory antibody responses in mice. Three different mosaic cVLP vaccines each composed of five CIDRα1 protein variants with varying degrees of sequence conservation of residues at and near the EPCR binding site, were tested. All mosaic cVLP vaccines induced functional antibodies comparable to those induced by matched cocktails of cVLPs decorated with the single CIDRα1 variant. No broadly reactive responses were observed. However, the vaccines did induce some cross-reactivity and inhibition within the CIDRα1 subclasses included in the vaccines, demonstrating potential use of the cVLP vaccine platform for the design of multivalent vaccines.

KW - Animals

KW - Protozoan Proteins/immunology

KW - Mice

KW - Vaccines, Virus-Like Particle/immunology

KW - Humans

KW - Endothelial Protein C Receptor/immunology

KW - Malaria Vaccines/immunology

KW - Plasmodium falciparum/immunology

KW - Antibodies, Protozoan/immunology

KW - Female

KW - Protein Domains

KW - Protein Binding

KW - Mice, Inbred BALB C

KW - Receptors, Cell Surface/immunology

KW - Malaria, Falciparum/prevention & control

U2 - 10.1371/journal.pone.0302243

DO - 10.1371/journal.pone.0302243

M3 - Journal article

C2 - 39046960

VL - 19

SP - e0302243

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 7

ER -