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 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 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 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.

scholarly journals Plasmodium falciparum-Specific Cellular Immune Responses after Immunization with the RTS,S/AS02D Candidate Malaria Vaccine in Infants Living in an Area of High Endemicity in Mozambique

2009 ◽  
Vol 77 (10) ◽  
pp. 4502-4509 ◽  
Author(s):  
Arnoldo Barbosa ◽  
Denise Naniche ◽  
John J. Aponte ◽  
M. Nelia Manaca ◽  
Inacio Mandomando ◽  
...  
Keyword(s):  
Immune Responses ◽  
Malaria Vaccine ◽  
Interleukin 2 ◽  
Vaccine Trial ◽  
Field Studies ◽  
Clinical Phase ◽  
Cellular Immune Responses ◽  
Ifn Γ ◽  
Cellular Immune ◽  
First Time

ABSTRACT Results from clinical trials in areas where malaria is endemic have shown that immunization with RTS,S/AS02A malaria vaccine candidate induces partial protection in adults and children and cellular effector and memory responses in adults. For the first time in a malaria vaccine trial, we sought to assess the cell-mediated immune responses to RTS,S antigen components in infants under 1 year of age participating in a clinical phase I/IIb trial of RTS,S/AS02D in Mozambique. Circumsporozoite protein (CSP)-specific responses were detected in approximately half of RTS,S-immunized infants and included gamma interferon (IFN-γ), interleukin-2 (IL-2), and combined IL-2/IL-4 responses. The median stimulation indices of cytokine-producing CD4+ and CD8+ cells were very low but significantly higher in RTS,S-immunized infants than in infants that received the comparator vaccine. Protection against subsequent malarial infection tended to be associated with a higher percentage of individuals with CSP-specific IL-2 in the supernatant (P = 0.053) and with higher CSP-specific IFN-γ-producing CD8+ T-cell responses (P = 0.07). These results report for the first time the detection of malaria-specific cellular immune responses after vaccination of infants less than 1 year of age and pave the way for future field studies of cellular immunity to malaria vaccine candidates.

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.

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