Faculty Opinions recommendation of Molecular basis of allele-specific efficacy of a blood-stage malaria vaccine: vaccine development implications.

2013 ◽  
Author(s):  
David Conway
Keyword(s):  
Molecular Basis ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Blood Stage ◽  
Allele Specific ◽  
Blood Stage Malaria

scholarly journals Molecular Basis of Allele-Specific Efficacy of a Blood-Stage Malaria Vaccine: Vaccine Development Implications

2012 ◽  
Vol 207 (3) ◽  
pp. 511-519 ◽  
Author(s):  
Amed Ouattara ◽  
Shannon Takala-Harrison ◽  
Mahamadou A. Thera ◽  
Drissa Coulibaly ◽  
Amadou Niangaly ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Blood Stage ◽  
Allele Specific ◽  
Blood Stage Malaria

scholarly journals Identification of a Potent Combination of Key Plasmodium falciparum Merozoite Antigens That Elicit Strain-Transcending Parasite-Neutralizing Antibodies

2012 ◽  
Vol 81 (2) ◽  
pp. 441-451 ◽  
Author(s):  
Alok K. Pandey ◽  
K. Sony Reddy ◽  
Tajali Sahar ◽  
Sonal Gupta ◽  
Hina Singh ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Neutralizing Antibodies ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Blood Stage ◽  
Content Type ◽  
Receptor Blocking ◽  
Erythrocyte Invasion ◽  
Invasion Inhibition ◽  
Blood Stage Malaria

ABSTRACTBlood-stage malaria vaccines that target singlePlasmodium falciparumantigens involved in erythrocyte invasion have not induced optimal protection in field trials. Blood-stage malaria vaccine development has faced two major hurdles, antigenic polymorphisms and molecular redundancy, which have led to an inability to demonstrate potent, strain-transcending, invasion-inhibitory antibodies. Vaccines that target multiple invasion-related parasite proteins may inhibit erythrocyte invasion more efficiently. Our approach is to develop a receptor-blocking blood-stage vaccine againstP. falciparumthat targets the erythrocyte binding domains of multiple parasite adhesins, blocking their interaction with their receptors and thus inhibiting erythrocyte invasion. However, with numerous invasion ligands, the challenge is to identify combinations that elicit potent strain-transcending invasion inhibition. We evaluated the invasion-inhibitory activities of 20 different triple combinations of antibodies mixedin vitroagainst a diverse set of six key merozoite ligands, including the novel ligandsP. falciparumapical asparagine-rich protein (PfAARP), EBA-175 (PfF2),P. falciparumreticulocyte binding-like homologous protein 1 (PfRH1), PfRH2, PfRH4, andPlasmodiumthrombospondin apical merozoite protein (PTRAMP), which are localized in different apical organelles and are translocated to the merozoite surface at different time points during invasion. They bind erythrocytes with different specificities and are thus involved in distinct invasion pathways. The antibody combination of EBA-175 (PfF2), PfRH2, and PfAARP produced the most efficacious strain-transcending inhibition of erythrocyte invasion against diverseP. falciparumclones. This potent antigen combination was selected for coimmunization as a mixture that induced balanced antibody responses against each antigen and inhibited erythrocyte invasion efficiently. We have thus demonstrated a novel two-step screening approach to identify a potent antigen combination that elicits strong strain-transcending invasion inhibition, supporting its development as a receptor-blocking malaria vaccine.

scholarly journals The Blood Stage Antigen RBP2-P1 of Plasmodium vivax Binds Reticulocytes and Is a Target of Naturally Acquired Immunity

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Anongruk Chim-Ong ◽  
Thitiporn Surit ◽  
Sittinont Chainarin ◽  
Wanlapa Roobsoong ◽  
Jetsumon Sattabongkot ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Binding Protein ◽  
Blood Stage ◽  
Content Type ◽  
Binding Inhibition ◽  
Erythrocyte Binding ◽  
Blood Stage Malaria

ABSTRACT The interactions between Plasmodium parasites and human erythrocytes are prime targets of blood stage malaria vaccine development. The reticulocyte binding protein 2-P1 (RBP2-P1) of Plasmodium vivax, a member of the reticulocyte binding protein family, has recently been shown to be highly antigenic in several settings endemic for malaria. Yet, its functional characteristics and the relevance of its antibody response in human malaria have not been examined. In this study, the potential function of RBP2-P1 as an invasion ligand of P. vivax was evaluated. The protein was found to be expressed in schizonts, be localized at the apical end of the merozoite, and preferentially bind reticulocytes over normocytes. Human antibodies to this protein also exhibit erythrocyte binding inhibition at physiologically relevant concentrations. Furthermore, RBP2-P1 antibodies are associated with lower parasitemia and tend to be higher in asymptomatic carriers than in patients. This study provides evidence supporting a role of RBP2-P1 as an invasion ligand and its consideration as a vaccine target.

Examining cellular immune responses to inform development of a blood-stage malaria vaccine

Parasitology ◽  
2016 ◽  
Vol 143 (2) ◽  
pp. 208-223 ◽  
Author(s):  
DANIELLE I. STANISIC ◽  
MICHAEL F. GOOD
Keyword(s):  
Immune Responses ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Clinical Symptoms ◽  
Field Studies ◽  
Blood Stage ◽  
Number Of Factors ◽  
Different Response ◽  
Cellular Immune ◽  
Blood Stage Malaria

SUMMARYNaturally acquired immunity to the blood-stage of the malaria parasite develops slowly in areas of high endemicity, but is not sterilizing. It manifests as a reduction in parasite density and clinical symptoms. Immunity as a result of blood-stage vaccination has not yet been achieved in humans, although there are many animal models where vaccination has been successful. The development of a blood-stage vaccine has been complicated by a number of factors including limited knowledge of human-parasite interactions and which antigens and immune responses are critical for protection. Opinion is divided as to whether this vaccine should aim to accelerate the acquisition of responses acquired following natural exposure, or whether it should induce a different response. Animal and experimental human models suggest that cell-mediated immune responses can control parasite growth, but these responses can also contribute to significant immunopathology if unregulated. They are largely ignored in most blood-stage malaria vaccine development strategies. Here, we discuss key observations relating to cell-mediated immune responses in the context of experimental human systems and field studies involving naturally exposed individuals and how this may inform the development of a blood-stage malaria vaccine.

scholarly journals New antigens for a multicomponent blood-stage malaria vaccine

2014 ◽  
Vol 6 (247) ◽  
pp. 247ra102-247ra102 ◽  
Author(s):  
Faith H. Osier ◽  
Margaret J. Mackinnon ◽  
Cécile Crosnier ◽  
Gregory Fegan ◽  
Gathoni Kamuyu ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Blood Stage ◽  
Transmission Season ◽  
Research Priority ◽  
Malaria Transmission Season ◽  
Development Pipeline ◽  
Blood Stage Malaria ◽  
Selection Of

An effective blood-stage vaccine against Plasmodium falciparum remains a research priority, but the number of antigens that have been translated into multicomponent vaccines for testing in clinical trials remains limited. Investigating the large number of potential targets found in the parasite proteome has been constrained by an inability to produce natively folded recombinant antigens for immunological studies. We overcame these constraints by generating a large library of biochemically active merozoite surface and secreted full-length ectodomain proteins. We then systematically examined the antibody reactivity against these proteins in a cohort of Kenyan children (n = 286) who were sampled at the start of a malaria transmission season and prospectively monitored for clinical episodes of malaria over the ensuing 6 months. We found that antibodies to previously untested or little-studied proteins had superior or equivalent potential protective efficacy to the handful of current leading malaria vaccine candidates. Moreover, cumulative responses to combinations comprising 5 of the 10 top-ranked antigens, including PF3D7_1136200, MSP2, RhopH3, P41, MSP11, MSP3, PF3D7_0606800, AMA1, Pf113, and MSRP1, were associated with 100% protection against clinical episodes of malaria. These data suggest not only that there are many more potential antigen candidates for the malaria vaccine development pipeline but also that effective vaccination may be achieved by combining a selection of these antigens.

scholarly journals A Phase 1 study of the blood-stage malaria vaccine candidate AMA1-C1/Alhydrogel® with CPG 7909, using two different formulations and dosing intervals

Vaccine ◽  
2009 ◽  
Vol 27 (31) ◽  
pp. 4104-4109 ◽  
Author(s):  
Ruth D. Ellis ◽  
Gregory E.D. Mullen ◽  
Mark Pierce ◽  
Laura B. Martin ◽  
Kazutoyo Miura ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Vaccine Candidate ◽  
Phase 1 ◽  
Blood Stage ◽  
Phase 1 Study ◽  
Malaria Vaccine Candidate ◽  
Dosing Intervals ◽  
Blood Stage Malaria

scholarly journals Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

2013 ◽  
Vol 82 (1) ◽  
pp. 152-164 ◽  
Author(s):  
K. Sony Reddy ◽  
Alok K. Pandey ◽  
Hina Singh ◽  
Tajali Sahar ◽  
Amlabu Emmanuel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Neutralizing Antibodies ◽  
Malaria Vaccine ◽  
Expression System ◽  
Full Length ◽  
Blood Stage ◽  
Parasite Protein ◽  
Content Type ◽  
Erythrocyte Binding ◽  
Blood Stage Malaria

ABSTRACTPlasmodium falciparumreticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number ofP. falciparumstrains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 inEscherichia colithat exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number ofP. falciparumstrains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies.P. falciparumhas the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwideP. falciparumstrains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.

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