Immunization with Recombinant Plasmodium falciparum Erythrocyte Membrane Protein 1 CIDRα1 Domains Induces Domain Subtype Inhibitory Antibodies

TY - JOUR

T1 - Immunization with Recombinant Plasmodium falciparum Erythrocyte Membrane Protein 1 CIDRα1 Domains Induces Domain Subtype Inhibitory Antibodies

AU - Turner, Louise

AU - Theander, Thor G.

AU - Lavstsen, Thomas

PY - 2018

Y1 - 2018

N2 - Plasmodium falciparum malaria pathogenesis is tied to the sequestration of parasites in the microvasculature. Parasite sequestration leading to severe malaria is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) binding to endothelial protein C receptor (EPCR) via its CIDR1 domains. CIDR1 domains are targets of naturally acquired immunity, and a vaccine eliciting antibodies inhibiting the EPCR binding of CIDR1 could potentially prevent disease and death from malaria. CIDR1 domains have diversified in sequence to escape immune recognition but preserved structure to maintain EPCR binding. The EPCR-binding CIDR1 domains separate into six major sequence types predicted to form a conserved structure in which only the amino acids essential for EPCR binding are highly conserved. Here, we investigated whether antibodies elicited by vaccination with single or multiple recombinant CIDR1 domains are able to bind and inhibit diverse CIDR1 domains. We found that EPCR binding-inhibitory antibodies to CIDR1 variants closely related to those used for vaccination are readily elicited, whereas antibodies binding distant CIDR1 variants are sporadically generated and are rarely inhibitory. Despite this, sequence similarity correlated poorly with the ability of induced antibodies to inhibit across diverse variants, and no continuous sequence regions of importance for cross-inhibitory antibodies could be identified. This suggested that epitopes of cross-variant inhibitory antibodies were predominantly conformational. Vaccination with immunogens engineered to focus immune responses to specific epitopes or an optimal choice of multiple CIDR1 variants may improve elicitation of broadly reactive and inhibitory antibody responses.

AB - Plasmodium falciparum malaria pathogenesis is tied to the sequestration of parasites in the microvasculature. Parasite sequestration leading to severe malaria is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) binding to endothelial protein C receptor (EPCR) via its CIDR1 domains. CIDR1 domains are targets of naturally acquired immunity, and a vaccine eliciting antibodies inhibiting the EPCR binding of CIDR1 could potentially prevent disease and death from malaria. CIDR1 domains have diversified in sequence to escape immune recognition but preserved structure to maintain EPCR binding. The EPCR-binding CIDR1 domains separate into six major sequence types predicted to form a conserved structure in which only the amino acids essential for EPCR binding are highly conserved. Here, we investigated whether antibodies elicited by vaccination with single or multiple recombinant CIDR1 domains are able to bind and inhibit diverse CIDR1 domains. We found that EPCR binding-inhibitory antibodies to CIDR1 variants closely related to those used for vaccination are readily elicited, whereas antibodies binding distant CIDR1 variants are sporadically generated and are rarely inhibitory. Despite this, sequence similarity correlated poorly with the ability of induced antibodies to inhibit across diverse variants, and no continuous sequence regions of importance for cross-inhibitory antibodies could be identified. This suggested that epitopes of cross-variant inhibitory antibodies were predominantly conformational. Vaccination with immunogens engineered to focus immune responses to specific epitopes or an optimal choice of multiple CIDR1 variants may improve elicitation of broadly reactive and inhibitory antibody responses.

KW - antigen diversity

KW - CIDRα1

KW - cross-reactive antibody

KW - EPCR

KW - malaria

KW - PfEMP1

KW - vaccine

U2 - 10.1128/iai.00435-18

DO - 10.1128/iai.00435-18

M3 - Journal article

C2 - 30150256

AN - SCOPUS:85055617545

SN - 0019-9567

VL - 86

JO - Infection and Immunity

JF - Infection and Immunity

IS - 11

M1 - e00435-18

ER -