Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated
            <i>Plasmodium falciparum</i>
            Protein PFF0165c

Olugbile, Sope; Kulangara, Caroline; Bang, Gilles; Bertholet, Sylvie; Suzarte, Edith; Villard, Viviane; Frank, Geraldine; Audran, R; Razaname, Alain; Nébié, Issa; Awobusuyi, Olugbenga; Spertini, François; Kajava, Andrey V.; Felger, Ingrid; Druilhe, Pierre; Corradin, Giampietro

doi:10.1128/iai.00652-09

Cited by 47 publications

(54 citation statements)

References 38 publications

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“…1A; see Table S1 in the supplemental material) were used to isolate human monoclonal and polyclonal antibodies. In addition, monoclonal antibodies were isolated on peptide 27, an alpha-helical coiled-coil from the vaccine candidate PFF0165c (34,39,61). Screening for monoclonal antibodies was performed by ELISA using 12-day supernatants of CD22…”

Section: Resultsmentioning

confidence: 99%

“…These were compared for wild-type (WT) and Fc domain mutant monoclonal antibodies to both MSP2 and an alpha-helical coiled-coil (peptide 27) from the gene PFF0165c. Peptide 27 has recently been identified to be a novel, highly conserved, P. falciparum vaccine candidate (34,39,61). Contrary to prediction, a remarkably high level of heterologous function by allele-specific MSP2 human antibodies was observed.…”

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confidence: 88%

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Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies

Stubbs¹,

Olugbile

Balam

et al. 2011

Infect Immun

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It is widely accepted that antibody responses against the human parasitic pathogen Plasmodium falciparum protect the host from the rigors of severe malaria and death. However, there is a continuing need for the development of in vitro correlate assays of immune protection. To this end, the capacity of human monoclonal and polyclonal antibodies in eliciting phagocytosis and parasite growth inhibition via Fc␥ receptor-dependent mechanisms was explored. In examining the extent to which sequence diversity in merozoite surface protein 2 (MSP2) results in the evasion of antibody responses, an unexpectedly high level of heterologous function was measured for allele-specific human antibodies. The dependence on Fc␥ receptors for opsonic phagocytosis and monocyte-mediated antibody-dependent parasite inhibition was demonstrated by the mutation of the Fc domain of monoclonal antibodies against both MSP2 and a novel vaccine candidate, peptide 27 from the gene PFF0165c. The described flow cytometry-based functional assays are expected to be useful for assessing immunity in naturally infected and vaccinated individuals and for prioritizing among blood-stage antigens for inclusion in blood-stage vaccines.Merozoite surface protein 2 (MSP2) is a leading Plasmodium falciparum vaccine candidate. Antibody responses to MSP2 have been associated with protection from malaria in humans (1,11,37,43,50,53) and afford protection in mouse models (35,46). However, extreme sequence diversity in MSP2 is considered an obstacle for vaccine design. Hundreds of alleles encoding MSP2 are classified into two main allelic families represented by the 3D7 and FC27/D10 MSP2 sequences (15,28,49,57). The coexistence of parasites bearing the dimorphic alleles at similar frequencies in globally disparate locations indicates their maintenance by selective pressures (9). Given that MSP2 is a blood-stage antigen, it is considered likely that sequence diversification may be driven by the host immune response by allele-specific antibodies. Consistent with this hypothesis, vaccine recipients in the Combination B phase IIb vaccine trial, whose humoral responses against the MSP2-3D7 allele were boosted, were rendered more susceptible than the placebo controls to parasitization with heterologous FC27-type parasites (16,19). Early studies showed that mouse monoclonal antibodies (MAbs) that discriminated between heterologous parasites affected homologous in vitro growth inhibition (7, 13). Curiously, there is scant evidence of the inability of allele-specific MAbs to inhibit heterologous parasites in vitro (45).Like other P. falciparum antigens, MSP2 antibody responses are skewed to cytophilic (IgG1 and IgG3) isotypes (37,43,50,53,54), which have been positively associated with protection from malaria (4,11,21,37,44,50,54). These isotypes bind via their Fc domain to Fc␥ receptors, thereby eliciting cellular immune responses of the innate immune system. Antibody opsonization of P. falciparum-infected erythrocytes and merozoites enhances their phagocytosis (6,12,22,30,3...

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Section: Resultsmentioning

confidence: 99%

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confidence: 88%

Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies

Stubbs¹,

Olugbile

Balam

et al. 2011

Infect Immun

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“…This could possibly result in the generation of conformational B-cell epitopes, but our results suggest that this is not a frequent occurrence, and in contrast to the dominance of conformational B-cell epitopes in globular proteins, linear epitopes predominate in MSP2 and presumably other intrinsically unstructured proteins. This is of particular relevance to malaria vaccine development, given the abundance of unstructured proteins in Plasmodium proteomes (16,33).…”

Section: Discussionmentioning

confidence: 99%

Antigenic Characterization of an Intrinsically Unstructured Protein, Plasmodium falciparum Merozoite Surface Protein 2

et al. 2012

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dMerozoite surface protein 2 (MSP2) is an abundant glycosylphosphatidylinositol (GPI)-anchored protein of Plasmodium falciparum, which is a potential component of a malaria vaccine. As all forms of MSP2 can be categorized into two allelic families, a vaccine containing two representative forms of MSP2 may overcome the problem of diversity in this highly polymorphic protein. Monomeric recombinant MSP2 is an intrinsically unstructured protein, but its conformational properties on the merozoite surface are unknown. This question is addressed here by analyzing the 3D7 and FC27 forms of recombinant and parasite MSP2 using a panel of monoclonal antibodies raised against recombinant MSP2. The epitopes of all antibodies, mapped using both a peptide array and by nuclear magnetic resonance (NMR) spectroscopy on full-length recombinant MSP2, were shown to be linear. The antibodies revealed antigenic differences, which indicate that the conserved N-and C-terminal regions, but not the central variable region, are less accessible in the parasite antigen. This appears to be an intrinsic property of parasite MSP2 and is not dependent on interactions with other merozoite surface proteins as the loss of some conserved-region epitopes seen using the immunofluorescence assay (IFA) on parasite smears was also seen on Western blot analyses of parasite lysates. Further studies of the structural basis of these antigenic differences are required in order to optimize recombinant MSP2 constructs being evaluated as potential vaccine components.

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“…This approach was adopted rather than taking a genome-wide approach, which predominantly includes intracellular proteins, because the role of intracellular proteins as targets of protective or functionally active Abs is unclear. Although it was demonstrated that immune responses against intracellular proteins can induce inhibition of in vitro parasite growth by ADCI mechanisms (66,67), we sought to focus on Ags that are likely to be direct targets of Abs to intact merozoites. Genome-wide approaches using high-throughput protein expression are also valuable and have identified Ags that may be important immune targets or biomarkers of immunity (15).…”

Section: Discussionmentioning

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

217

240

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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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Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c

Cited by 47 publications

References 38 publications

Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies

Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies

Antigenic Characterization of an Intrinsically Unstructured Protein, Plasmodium falciparum Merozoite Surface Protein 2

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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