PfEMP1 as a target of human immunity and a vaccine candidate against malaria

The development of an effective malaria vaccine is a major priority for malaria control and elimination. There is a strong rationale that an effective malaria vaccine is achievable; immunity can be induced in experimental animal models and humans living in malaria-endemic regions acquire natural immunity to malaria after repeated infections [1]. Human immunity appears to predominantly target the blood-stage of the Plasmodium falciparum lifecycle when parasites infect red blood cells (RBCs) and replicate within them. Antibodies are an important component of this immunity as demonstrated by studies showing that purified antibodies from immune adults can clear parasitemia and resolve symptoms when administered to nonimmune children and adults with malaria. P. falciparum is the major cause of human malaria and a number of antigens have been investigated as potential vaccine candidates. Candidate blood-stage antigens include those on the surface of merozoites that invade RBCs (reviewed in [1]) and parasitederived proteins expressed on the surface of P. falciparum-infected RBCs (iRBCs) [2]. Recent collective evidence strongly points to a protein expressed on the iRBC surface, known as P. falciparum erythrocyte membrane protein 1 (PfEMP1) [3], as a major target of human immunity, as well as being a major virulence protein in the pathogenesis of malaria. Despite the clear importance of PfEMP1 as an immune target, antigenic diversity is a key obstacle that must be overcome for PfEMP1 to be pursued as a major malaria vaccine candidate. PfEMP1 is a major target of human immunity During intraerythrocytic development, multiple polymorphic parasite-derived antigens are expressed on the surface of iRBCs that are collectively known as variant surface antigens (VSAs) [4]. Antibodies are naturally acquired to VSAs after exposure to P. falciparum infection and appear to play an important role in mediating acquired immunity to P. falciparum malaria [4,5]. Many VSAs have been identified, including PfEMP1, RIFIN, STEVOR, SURFIN and possibly others. Of these, the most extensively studied VSA is PfEMP1, a large (200–300 kDa) multidomain protein that has been shown to be targeted by naturally acquired antibodies [3]. PfEMP1 is encoded by the highly polymorphic var multigene family (~60 genes per genome), with different var genes encoding PfEMP1 variants with a range of antigenic and adhesive properties [6]. PfEMP1 is an important virulence protein that mediates the adhesion of iRBCs to vascular endothelial cells, as well as uninfected RBCs to form rosettes. This adhesion facilitates the sequestration of iRBCs in various organs such as the brain, lung and the placenta [2]. These virulence properties of PfEMP1 contribute substantially to the pathogenesis of P. falciparum malaria. Due to the number of different VSAs present on the iRBC surface, the significance of PfEMP1 relative to other VSAs as a target of human antibodies has been difficult to quantify. The majority of studies have relied on the use of recombinant purified PfEMP1 domains in standard immunoassays. Such PfEMP1 as a target of human immunity and a vaccine candidate against malaria