Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 10, 2712
eCollection

Plasmodium falciparum Blood Stage Antimalarial Vaccines: An Analysis of Ongoing Clinical Trials and New Perspectives Related to Synthetic Vaccines

Affiliations
Review

Plasmodium falciparum Blood Stage Antimalarial Vaccines: An Analysis of Ongoing Clinical Trials and New Perspectives Related to Synthetic Vaccines

David Ricardo Salamanca et al. Front Microbiol.

Abstract

Plasmodium falciparum malaria is a disease causing high morbidity and mortality rates worldwide, mainly in sub-Saharan Africa. Candidates have been identified for vaccines targeting the parasite's blood stage; this stage is important in the development of symptoms and clinical complications. However, no vaccine that can directly affect morbidity and mortality rates is currently available. This review analyzes the formulation, methodological design, and results of active clinical trials for merozoite-stage vaccines, regarding their safety profile, immunological response (phase Ia/Ib), and protective efficacy levels (phase II). Most vaccine candidates are in phase I trials and have had an acceptable safety profile. GMZ2 has made the greatest progress in clinical trials; its efficacy has been 14% in children aged less than 5 years in a phase IIb trial. Most of the available candidates that have shown strong immunogenicity and that have been tested for their protective efficacy have provided good results when challenged with a homologous parasite strain; however, their efficacy has dropped when they have been exposed to a heterologous strain. In view of these vaccines' unpromising results, an alternative approach for selecting new candidates is needed; such line of work should be focused on how to increase an immune response induced against the highly conserved (i.e., common to all strains), functionally relevant, protein regions that the parasite uses to invade target cells. Despite binding regions tending to be conserved, they are usually poorly antigenic and/or immunogenic, being frequently discarded as vaccine candidates when the conventional immunological approach is followed. The Fundación Instituto de Inmunología de Colombia (FIDIC) has developed a logical and rational methodology based on including conserved high-activity binding peptides (cHABPs) from the main P. falciparum biologically functional proteins involved in red blood cell (RBC) invasion. Once appropriately modified (mHABPs), these minimal, subunit-based, chemically synthesized peptides can be used in a system covering the human immune system's main genetic variables (the human leukocyte antigen HLA-DR isotype) inducing a suitable, immunogenic, and protective immune response in most of the world's populations.

Keywords: Plasmodium falciparum; antimalarial vaccine; clinical trial; immunogenicity; malaria; merozoite; vaccine.

Figures

FIGURE 1
FIGURE 1
Plasmodium falciparum life cycle. (A) Liver stage. Sporozoites (Spz) inoculated during the bite of a female Anopheles mosquito migrate to hepatic cells through the host’s blood stream, thereby infecting hepatocytes where they reproduce (30,000–50,000 per Spz) (pre-erythrocyte cycle) and become transformed into merozoites (Mrz). When Mrz are released into the blood stream, they invade the red blood cells (RBCs) (erythrocyte cycle), producing 30–50 new Mrz every 48 h during which the cycle lasts, inducing the release of subproducts, immune system molecule production, and the symptoms of the disease, which can cause death in some people. Some Mrz become gametocytes, which then become digested by other mosquitos during fresh biting to start their sexual cycle and produce new Spz. (B) Blood stage. Mrz roll over RBC and adhere to their surface. They become reorientated toward their apical pole by high-affinity interactions between microneme proteins and erythrocyte receptors, thereby deforming the RBC membrane to create a tight junction (TJ) to enable their entry. The rhoptry proteins are then released onto the RBC surface, and the parasitophorous vacuole membrane (PVM) starts forming; the parasite progressively develops after entry into ring, trophozoite, and schizont forms. (C) Mrz interaction with ligands and their erythrocyte receptors. The MSP1 complex interacts with BAND3-GPYA, EBA-140 with GYPC, EBA-175 with GYPA, EBA-181 with the E receptor, EBL1 with GYPB, RH1 with the Y receptor, RH2b with the Z receptor, RH4 with CR1, and RH5 with BSG. GYPA: glycophorin A, GYPB: glycophorin B, GYPC: glycophorin C, BSG: basigin, PVM: parasitophorous vacuole membrane, CR1: complement receptor 1.
FIGURE 2
FIGURE 2
Scheme for proteins used as candidates for an antimalarial vaccine (I). Color code: blue, whole protein; yellow, functional domain; orange, N-terminal signal peptide; green, conserved high-activity binding peptides (cHABPs) with Fundación Instituto de Inmunología de Colombia (FIDIC)-assigned coding; purple, cytoplasmic domain. (A) MSP3-LSP vaccine, including B1, B2, and B3 domains (yellow). (B) P27A vaccine, including ring domain (yellow). (C) BK-SE36 vaccine. (D) AMA-1-DiCo vaccine, including domain I (purple), domain II (red), variable amino acids (pink), and cHABPs 4325 (green) and 4313 (magenta). PDB 4R19 (Lim et al., 2014). (E) PAMVAC and PRIMVAC vaccines. Top: Protein scheme, CIDRα1 (cysteine-rich inter-domain regions α1), C2 (C2 domain), and Duffy binding-like (DBL) domain. Bottom: Protein structure, including the NTS region (blue), whole protein (green), and cHABPs 6510 (purple) and 6512 (orange). PDB 2XU0.
FIGURE 3
FIGURE 3
Scheme for the proteins used as candidates for an antimalarial vaccine (II). Color code according to that used in Figure 2. (A) PfPEBS vaccine. (B) Top: Scheme for the EBA-175 RII NG vaccine. Bottom: Protein structure, including region II surface, F1 (green) and F2 domains (pink), and conserved high-activity binding peptides (cHABPs) 1779 (red) and 1783 (yellow), PDB 1ZRO (Tolia et al., 2005). (C) GMZ2 vaccine, including the scheme for proteins MSP3 and GLURP according to the color code used for Figure 2. (D) ChAd63/MVA RH5 vaccine. Top: pSG2 plasmid, including the kanamycin resistance gene (KanR), cytomegalovirus (CMV) with the associated intron A (CMVintA), bovine growth hormone (bGH) with polyadenylation (bGH PolyA), Escherichia coli β-galactosidase (ColE1), and the RH5-encoding gene. Bottom: Surface and ribbon for the RH5 protein with cHABPs 36727 (magenta), 36728 (green), 36735 (yellow), 36736 (orange), 36740 (red), and 36742 (blue). PDB 4WAT (Chen et al., 2014).

Similar articles

See all similar articles

References

    1. Arévalo-Pinzón G., Curtidor H., Muñoz M., Patarroyo M. A., Bermudez A., Patarroyo M. E. (2012). A single amino acid change in the Plasmodium falciparum RH5 (PfRH5) human RBC binding sequence modifies its structure and determines species-specific binding activity. Vaccine 30 637–646. 10.1016/j.vaccine.2011.11.012 - DOI - PubMed
    1. Audran R., Cachat M., Lurati F., Soe S., Leroy O., Corradin G., et al. (2005). Phase I malaria vaccine trial with a long synthetic peptide derived from the merozoite surface protein 3 antigen. Infect. Immun. 73 8017–8026. 10.1128/IAI.73.12.8017-8026.2005 - DOI - PMC - PubMed
    1. Baum J., Chen L., Healer J., Lopaticki S., Boyle M., Triglia T., et al. (2009). Reticulocyte-binding protein homologue 5 – An essential adhesin involved in invasion of human erythrocytes by Plasmodium falciparum. Int. J. Parasitol. 39 371–380. 10.1016/j.ijpara.2008.10.006 - DOI - PubMed
    1. Belachew E. B. (2018). Immune response and evasion mechanisms of Plasmodium falciparum parasites. J. Immunol. Res. 2018:6529681. 10.1155/2018/6529681 - DOI - PMC - PubMed
    1. Bélard S., Issifou S., Hounkpatin A. B., Schaumburg F., Ngoa U. A., Esen M., et al. (2011). A randomized controlled phase Ib Trial of the malaria vaccine candidate GMZ2 in African children. PLoS One 6:e22525. 10.1371/journal.pone.0022525 - DOI - PMC - PubMed

LinkOut - more resources

Feedback