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Immunization with virus-like particles conjugated to CIDR?1 domain of Plasmodium falciparum erythrocyte membrane protein 1 induces inhibitory antibodies.

ABSTRACT: BACKGROUND:During the erythrocytic cycle, Plasmodium falciparum malaria parasites express P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) that anchor the infected erythrocytes (IE) to the vascular lining of the host. The CIDR?1 domain of PfEMP1 is responsible for binding host endothelial protein C receptor (EPCR), and increasing evidence support that this interaction triggers severe malaria, accounting for the majority of malaria-related deaths. In high transmission regions, children develop immunity to severe malaria after the first few infections. This immunity is believed to be mediated by antibodies targeting and inhibiting PfEMP1, causing infected erythrocytes to circulate and be cleared in the spleen. The development of immunity to malaria coincides with acquisition of broad antibody reactivity across the CIDR?1 protein family. Altogether, this identifies CIDR?1 as an important vaccine target. However, the antigenic diversity of the CIDR?1 domain family is a challenge for vaccine development. METHODS:Immune responses in mice vaccinated with Virus-Like Particles (VLP) presenting CIDR?1 antigens were investigated. Antibody reactivity was tested to a panel of recombinant CIDR?1 domains, and the antibodies ability to inhibit EPCR binding by the recombinant CIDR?1 domains was tested in Luminex-based multiplex assays. RESULTS:VLP-presented CIDR?1.4 antigens induced a rapid and strong IgG response capable of inhibiting EPCR-binding of multiple CIDR?1 domains mainly within the group A CIDR?1.4-7 subgroups. CONCLUSIONS:The study observations mirror those from previous CIDR?1 vaccine studies using other vaccine constructs and platforms. This suggests that broad CIDR?1 antibody reactivity may be achieved through vaccination with a limited number of CIDR?1 variants. In addition, this study suggest that this may be achieved through vaccination with a human compatible VLP vaccine platform.

SUBMITTER: Harmsen C

PROVIDER: S-EPMC7106694 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Immunization with virus-like particles conjugated to CIDRα1 domain of Plasmodium falciparum erythrocyte membrane protein 1 induces inhibitory antibodies.

Harmsen Charlotte C Turner Louise L Thrane Susan S Sander Adam F AF Theander Thor G TG Lavstsen Thomas T

Malaria journal 20200330 1

<h4>Background</h4>During the erythrocytic cycle, Plasmodium falciparum malaria parasites express P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) that anchor the infected erythrocytes (IE) to the vascular lining of the host. The CIDRα1 domain of PfEMP1 is responsible for binding host endothelial protein C receptor (EPCR), and increasing evidence support that this interaction triggers severe malaria, accounting for the majority of malaria-related deaths. In high transmission regions, childr ...[more]

PMID: 32228596

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Project description:VAR2CSA, a member of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family, is a leading candidate for use in vaccines to protect first-time mothers from placental malaria (PM). VAR2CSA, which is comprised of a series of six Duffy binding-like (DBL) domains, binds chondroitin sulfate A (CSA) on placental syncytiotrophoblast. Several recombinant DBL domains have been shown to bind CSA. In order to identify and develop recombinant proteins suitable for clinical development, DBL2X and DBL3X, as well as their respective third subdomain (S3) from the FCR3 parasite clone, were expressed in Escherichia coli, refolded, and purified. All but DBL3X-S3 recombinant proteins bound to CSA expressed on Chinese hamster ovary (CHO)-K1 cells but not to CHO-pgsA745 cells, which are CSA negative as determined by flow cytometry. All but DBL3X-S3 bound to CSA on chondroitin sulfate proteoglycan (CSPG) as determined by surface plasmon resonance (SPR) analysis. Purified IgG from rats and rabbits immunized with these four recombinant proteins bound homologous and some heterologous parasite-infected erythrocytes (IE). Using a novel flow cytometry inhibition-of-binding assay (flow-IBA), antibodies against DBL3X-S3 inhibited 35% and 45% of IE binding to CSA on CHO-K1 cells compared to results for soluble CSA (sCSA) and purified multigravida (MG) IgG, respectively, from areas in Tanzania to which malaria is endemic. Antibodies generated against the other domains provided little or no inhibition of IE binding to CSA on CHO-K1 cells as determined by the flow cytometry inhibition-of-binding assay. These results demonstrate for the first time the ability to identify antibodies to VAR2CSA DBL domains and subdomains capable of inhibiting VAR2CSA parasite-IE binding to CSA by flow cytometry. The flow cytometry inhibition-of-binding assay was robust and provided an accurate, reproducible, and reliable means to identify blocking of IE binding to CSA and promises to be significant in the development of a vaccine to protect pregnant women.

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Immunization with virus-like particles conjugated to CIDR?1 domain of Plasmodium falciparum erythrocyte membrane protein 1 induces inhibitory antibodies.

Publications

Immunization with virus-like particles conjugated to CIDRα1 domain of Plasmodium falciparum erythrocyte membrane protein 1 induces inhibitory antibodies.

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