Discovery of GAMA, a Plasmodium falciparum Merozoite Micronemal Protein, as a Novel Blood-Stage Vaccine Candidate Antigen

Arumugam, Thangavelu U; Takeo, Satoru; Yamasaki, Tsutomu; Thonkukiatkul, Amporn; Miura, Kazutoyo; Otsuki, Hitoshi; Zhou, Hong; Long, Carole A.; Sattabongkot, Jetsumon; Thompson, J. K.; Wilson, Danny W.; Beeson, James G.; Healer, Julie; Crabb, Brendan S.; Cowman, Alan F.; Torii, Motomi; Tsuboi, Takafumi

doi:10.1128/iai.05412-11

Cited by 70 publications

(97 citation statements)

References 37 publications

(55 reference statements)

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“…Female BALB/c mice (DaehanBiolink Co., Eumsung, ROK) were used at 5 to 7 weeks of age. Groups of three mice were injected intraperitoneally with 20 g of MSP1P-30, -42, -33, and -19, or MSP1-19, and phosphatebuffered saline (PBS) with Freund's complete adjuvant (Sigma-Aldrich, St. Louis, MO) as described previously (31). Booster injections were given 3 and 6 weeks after the priming using the same amount of antigen with Freund's incomplete adjuvant (Sigma-Aldrich), and mouse sera were collected 2 weeks after the final boost.…”

Section: Methodsmentioning

confidence: 99%

“…Eight fragments of DNA encoding PvMSP1P-83A, -83B, -83C, -30, -38, -42, -33, and -19 were amplified and cloned into pEU-E01-His-TEV-MCS vector (CellFree Sciences), and the cloned inserts were sequenced using an ABI 3700 genetic analyzer (Genotech, Daejeon, South Korea). Those proteins, including PvDBP region II (PvDBPII) and PvMSP1-19, were also expressed using a WGCF expression system (CellFree Sciences) and purified using Ni-affinity chromatography as described previously (31)(32)(33).…”

Section: Methodsmentioning

confidence: 99%

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The Plasmodium vivax Merozoite Surface Protein 1 Paralog Is a Novel Erythrocyte-Binding Ligand of P. vivax

et al. 2013

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dMerozoite surface protein 1 of Plasmodium vivax (PvMSP1), a glycosylphosphatidylinositol-anchored protein (GPI-AP), is a malaria vaccine candidate for P. vivax. The paralog of PvMSP1, named P. vivax merozoite surface protein 1 paralog (PvMSP1P; PlasmoDB PVX_099975), was recently identified and predicted as a GPI-AP. The similarities in genetic structural characteristics between PvMSP1 and PvMSP1P (e.g., size of open reading frames, two epidermal growth factor-like domains, and GPI anchor motif in the C terminus) led us to study this protein. In the present study, different regions of the PvMSP1P protein, demarcated based on the processed forms of PvMSP1, were expressed successfully as recombinant proteins [i.e., 83 (A, B, and C), 30, 38, 42, 33, and 19 fragments]. We studied the naturally acquired immune response against each fragment of recombinant PvMSP1P and the potential ability of each fragment to bind erythrocytes. The N-terminal fragment (83A) and two C-terminal fragments (33 and 19) reacted strongly with sera from P. vivax-infected patients, with 50 to 68% sensitivity and 95 to 96% specificity, respectively. Due to colocalization of PvMSP1P with PvMSP1, we supposed that PvMSP1P plays a similar role as PvMSP1 during erythrocyte invasion. An in vitro cytoadherence assay showed that PvMSP1P, especially the 19-kDa C-terminal region, could bind to erythrocytes. We also found that human sera from populations naturally exposed to vivax malaria and antisera obtained by immunization using the recombinant molecule PvMSP1P-19 inhibited in vitro binding of human erythrocytes to PvMSP1P-19. These results provide further evidence that the PvMSP1P might be an essential parasite adhesion molecule in the P. vivax merozoite and is a potential vaccine candidate against P. vivax.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Plasmodium vivax Merozoite Surface Protein 1 Paralog Is a Novel Erythrocyte-Binding Ligand of P. vivax

et al. 2013

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“…Recently, a few reports have demonstrated that targeting combinations of merozoite antigens (including EBA and PfRH) yielded potent invasion inhibition (15,19,20). However, those studies did not demonstrate invasion-inhibitory efficacy against heterologous P. falciparum clones, which exhibit different invasion phenotypes.…”

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confidence: 97%

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

et al. 2013

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Blood-stage malaria vaccines that target single Plasmodium falciparum antigens 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 against P. falciparum that 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 invasioninhibitory activities of 20 different triple combinations of antibodies mixed in vitro against a diverse set of six key merozoite ligands, including the novel ligands P. falciparum apical asparagine-rich protein (PfAARP), EBA-175 (PfF2), P. falciparum reticulocyte binding-like homologous protein 1 (PfRH1), PfRH2, PfRH4, and Plasmodium thrombospondin 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 diverse P. falciparum clones. 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.

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“…The quality of protein expression and folding had been validated previously for some of the protein constructs used by demonstrating that vaccine-induced Abs raised against the recombinant protein recognize native protein (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37); vaccine-induced Abs have functional antiparasite activity in growthinhibition assays (GIAs) or Ab-dependent cellular-inhibition (ADCI) assays (12,28,30,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43); or the recombinant protein has appropriate biological function by binding its receptor (25,28,34,35,38,39) (Supplemental Table I). Validation of WGCF as an appropriate system for expression of P. falciparum merozoite proteins has also been established in several ways.…”

Section: Expression Of Ragsmentioning

confidence: 99%

Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

Richards

Arumugam

Reiling

et al. 2013

The Journal of Immunology

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The development of effective malaria vaccines and immune biomarkers of malaria is a high priority for malaria control and elimination. Ags expressed by merozoites of Plasmodium falciparum are likely to be important targets of human immunity and are promising vaccine candidates, but very few Ags have been studied. We developed an approach to assess Ab responses to a comprehensive repertoire of merozoite proteins and investigate whether they are targets of protective Abs. We expressed 91 recombinant proteins, located on the merozoite surface or within invasion organelles, and screened them for quality and reactivity to human Abs. Subsequently, Abs to 46 proteins were studied in a longitudinal cohort of 206 Papua New Guinean children to define Ab acquisition and associations with protective immunity. Ab responses were higher among older children and those with active parasitemia. High-level Ab responses to rhoptry and microneme proteins that function in erythrocyte invasion were identified as being most strongly associated with protective immunity compared with other Ags. Additionally, Abs to new or understudied Ags were more strongly associated with protection than were Abs to current vaccine candidates that have progressed to phase 1 or 2 vaccine trials. Combinations of Ab responses were identified that were more strongly associated with protective immunity than responses to their single-Ag components. This study identifies Ags that are likely to be key targets of protective human immunity and facilitates the prioritization of Ags for further evaluation as vaccine candidates and/or for use as biomarkers of immunity in malaria surveillance and control.

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Discovery of GAMA, a Plasmodium falciparum Merozoite Micronemal Protein, as a Novel Blood-Stage Vaccine Candidate Antigen

Cited by 70 publications

References 37 publications

The Plasmodium vivax Merozoite Surface Protein 1 Paralog Is a Novel Erythrocyte-Binding Ligand of P. vivax

The Plasmodium vivax Merozoite Surface Protein 1 Paralog Is a Novel Erythrocyte-Binding Ligand of P. vivax

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

Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

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