Safety and Immunogenicity of a Recombinant Nonglycosylated Erythrocyte Binding Antigen 175 Region II Malaria Vaccine in Healthy Adults Living in an Area Where Malaria Is Not Endemic

Abstract

Erythrocyte binding antigen region II (EBA-175) is a conserved antigen of Plasmodium falciparum that is involved in binding of the parasite to the host's erythrocytes. We evaluated the safety and immunogenicity of a recombinant EBA-175 vaccine with aluminum phosphate adjuvant in healthy young adults living in the United States. Eighteen subjects/group received ascending doses (5, 20, 80, or 160 g) of the vaccine at 0, 1, and 6 months; 8 subjects received placebo. Most of the injection site and systemic reactions were mild to moderate in intensity. After 2 or 3 doses of the vaccine at any concentration, antibody levels measured by enzyme-linked immunosorbent assay were significantly higher than those for the placebo group. Sera from subjects who received 3 doses of the vaccine at any concentration inhibited the growth of erythrocyte-stage P. falciparum at low levels compared to sera from placebo recipients or preimmune sera. In conclusion, the EBA-175 vaccine with adjuvant was safe and immunogenic in malaria-naïve subjects.The morbidity and mortality associated with malaria continue to exact a heavy price on many developing nations. The World Health Organization (WHO) estimates that 3.3 billion individuals live in areas where malaria is endemic, with 247 million cases and a million deaths reported for the year 2006 (41). In 1998, the Roll Back Malaria Partnership was launched to coordinate international malaria containment efforts and included the wide dissemination of long-lasting insecticidal nets, artemisinin-based combination therapy, indoor residual spraying of insecticide, and intermittent preventive treatment in pregnancy. In 2006, the success of implementing these interventions was variable, with some countries reporting a 50% decrease in the number of malaria cases and other countries reporting stable levels of transmission (5,8,13,41).Some pieces missing from the available armamentarium to fight malaria are safe and effective vaccines. Plasmodium falciparum is the species associated with the greatest morbidity and mortality. The approach to the development of a P. falciparum vaccine has paralleled the multistage nature of P. falciparum infections: preerythrocytic vaccines target the sporozoite or its antigens to achieve protection from infection; erythrocytic vaccines target the merozoite antigens to achieve protection from severe disease; and transmission-blocking vaccines utilize the gametocyte, zygote, or ookinete antigens to prevent sporogenic development in the vector (4,11,15,16,34,35,40). A multicomponent or multistage vaccine has also been proposed as a solution to the heterogeneity of the host's immune response and the parasite antigens.One antigen of interest in the development of P. falciparum erythrocytic vaccines is the erythrocyte binding antigen 175 (EBA-175). EBA-175 was the first P. falciparum ligand identified to have a role in high-affinity binding of the merozoite to the host's red blood cells (RBCs) (1, 7). EBA-175 binds to the RBC glycophorin A sialic acid residues, and the interac...

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

“…On the other hand, EBA-175 RII (where cHABPs 1779 and 1783 are located) is recognised by antibodies in individuals having naturally acquired immunity in an age-dependent manner and inhibits invasion of P. falciparum clinical isolates to some degree (Okenu et al, 2000;El Sahly et al, 2010;Badiane et al, 2013;Irani et al, 2015). High-titre antibodies against EBA-175 RII are associated with protection from clinical malaria in children (Okenu et al, 2000;McCarra et al, 2011), although such association is not clear in some studies or has not been observed in groups having low incidence of disease (Osier et al, 2008;Richards et al, 2010) It has been suggested that EBA-175 RII polymorphism has shown immune selection aimed at maintaining genetic diversity in parasite populations.…”

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“…EBA175-RII is a target for invasion inhibitory antibodies [17-21] and the EBA175-GypA interaction is a major RBC invasion pathway [19]. It has also become a leading malaria vaccine candidate [22,23], thus immunogenic epitopes within EBA175-RII should be exploited as potential vaccine candidates.…”

“…The crystal structure of EBA175-RII showing (A) the overlap between the predicted CD8+ epitope (aa 553-561) and the glycan binding sites at residues Lys-553 and Met-554, (B) the overlap between the predicted CD4+ epitope (aa 440-456) and the glycan binding sites at residue Asp-442, (C) the overlap between the predicted BCE (aa [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and the glycan binding sites at residues Lys-28, Asn-29, Arg-31, Ser-32 and Asn-33, (D) the overlap between the predicted BCE (aa 420-440) and the glycan binding sites at residue Lys-439 and (E) the overlap between the predicted BCE (aa 528-547) and the glycan binding sites at residues Gln-542 and Tyr-546.…”

The Impact of Immune Responses on the Asexual Erythrocytic Stages of Plasmodium and the Implication for Vaccine Development

“…The analysis of sera from malaria-endemic areas for the presence of EBA-175 specific antibodies revealed some association with protection in children that have higher antibody titers (reviewed in (Fowkes et al, 2010)). Recently, an EBA-175 based vaccine yielded some clinical efficacy (El Sahly et al, 2010).…”