Abstract
BackgroundDuring 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, 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 CIDRα1 protein family. Altogether, this identifies CIDRα1 as an important vaccine target. However, the antigenic diversity of the CIDRα1 domain family is a challenge for vaccine development.MethodsImmune responses in mice vaccinated with Virus-Like Particles (VLP) presenting CIDRα1 antigens were investigated. Antibody reactivity was tested to a panel of recombinant CIDRα1 domains, and the antibodies ability to inhibit EPCR binding by the recombinant CIDRα1 domains was tested in Luminex-based multiplex assays.ResultsVLP-presented CIDRα1.4 antigens induced a rapid and strong IgG response capable of inhibiting EPCR-binding of multiple CIDRα1 domains mainly within the group A CIDRα1.4–7 subgroups.ConclusionsThe study observations mirror those from previous CIDRα1 vaccine studies using other vaccine constructs and platforms. This suggests that broad CIDRα1 antibody reactivity may be achieved through vaccination with a limited number of CIDRα1 variants. In addition, this study suggest that this may be achieved through vaccination with a human compatible VLP vaccine platform.
Highlights
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
Production Virus-Like Particles (VLP)‐based CIDRα1 vaccines Two recombinant CIDRα1 proteins both derived from the HB3var03 PfEMP1 CIDRα1.4 sequence were produced with a SpyCatcher protein sequence in either the N-terminal or the C-terminal (Fig. 1)
Analysis of the IgG reactivity to the CIDRα1 domain used as immunogen The two VLP based CIDRα1.4 vaccines and two vaccines containing the corresponding soluble proteins were administered by intramuscular injection to BALB/c mice over three immunizations with 3-week intervals
Summary
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. 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. Young children who have acquired immunity to severe infections are still susceptible to less severe malaria episodes and immunity against these gradually forms during childhood [4] This development of immunity can be explained by a gradual acquisition of IgG against variable polymorphic proteins expressed on the surface of infected erythrocytes [5,6,7,8,9]. Members of the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family are considered main targets of this immunity These proteins are anchored in the erythrocyte membrane exposing their large N-terminal to engage with receptors on endothelial cells (reviewed in [10]). These antibodies are thought to be important mediators of immunity [11,12,13,14]
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