Fixed, epitope-specific, cytophilic antibody response to the polymorphic block 2 domain of thePlasmodium falciparum merozoite surface antigen MSP-1 in humans living in a malaria-endemic area

Jouin, H; Rogier, Christophe; Trape, Jean‐François; Mercereau‐Puijalon, Odile

doi:10.1002/1521-4141(200102)31:2<539::aid-immu539>3.0.co;2-1

Cited by 32 publications

(50 citation statements)

References 30 publications

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“…The frequency of MSP-1 19 antibodies seen in this work is closer to that observed in The Gambia (11), in Sudan (7), and in Kenya (4). Antibody to MSP-1 block 1 antigen was detected in only a few individuals (four in April and nine in November), thus extending earlier observations of low antibody prevalence to block 1 in other cohorts in The Gambia and Sudan (7,11) and of others in Senegal (where a synthetic peptide containing part of the block 1 sequence was used [24]). These findings indicate that although block 1 is conserved, it may be a poor immunogen and that antibody responses to block 1 antigen are not boosted by natural P. falciparum infections.…”

Section: Discussionsupporting

confidence: 82%

Antibodies to the N-Terminal Block 2 ofPlasmodium falciparumMerozoite Surface Protein 1 Are Associated with Protection against Clinical Malaria

et al. 2004

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This longitudinal prospective study shows that antibodies to the N-terminal block 2 region of the Plasmodium falciparum merozoite surface protein 1 (MSP-1) are associated with protection against clinical malaria in an area of stable but seasonal malaria transmission of Ghana. Antibodies to the block 2 region of MSP-1 were measured in a cohort of 280 children before the beginning of the major malaria transmission season. The cohort was then actively monitored for malaria, clinically and parasitologically, over a period of 17 months. Evidence is presented for an association between antibody responses to block 2 and a significantly reduced risk of subsequent clinical malaria. Furthermore, statistical survival analysis provides new information on the duration of the effect over time. The results support a conclusion that the block 2 region of MSP-1 is a target of protective immunity against P. falciparum and, thus, a promising new candidate for the development of a malaria vaccine.

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Section: Discussionsupporting

confidence: 82%

Antibodies to the N-Terminal Block 2 ofPlasmodium falciparumMerozoite Surface Protein 1 Are Associated with Protection against Clinical Malaria

et al. 2004

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“…For the three MSP1 block 2-derived Ags, the in vitro Ab profiles did not mirror the IgG3-skewed plasma profile (7,26,37). All four IgG subclasses were produced in vitro in response to these Ags.…”

Section: Discussionmentioning

confidence: 86%

“…The 10-fold-higher Ag concentration needed to promote in vitro IgG secretion compared to the concentrations of other recombinants may be indirect evidence of this in vitro priming. On the other hand, we have previously shown that the fine specificity of plasma Ab to MSP1 block 2 is stable over long periods of time despite reexposure to numerous variant MSP1 Ags (26). This suggests that there is an imprinted response that FIG.…”

Section: Discussionmentioning

confidence: 97%

“…The four allelic MSP1 19 variants (Q-KNG, E-KNG, Q-TSR, and E-TSR) were produced in the yeast Saccharomyces cerevisiae (27). (ii) Three allelic forms of MSP1 block 2, a polymorphic MSP1 domain located close to the N terminus, were cloned and expressed in Escherichia coli as glutathione transferase (GST) fusion proteins (26). The three variants were derived from the Palo Alto FUP, Wellcome, and Ghana RO33 strains and represent the K1, MAD20, and RO33 families, respectively (31).…”

Section: Methodsmentioning

confidence: 99%

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Regulation of Antigen-Specific Immunoglobulin G Subclasses in Response to Conserved and PolymorphicPlasmodium falciparumAntigens in an In Vitro Model

Garraud¹,

Perraut²,

Diouf³

et al. 2002

Infect Immun

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Cytophilic antibodies (Abs) play a critical role in protection against Plasmodium falciparum blood stages, yet little is known about the parameters regulating production of these Abs. We used an in vitro culture system to study the subclass distribution of antigen (Ag)-specific immunoglobulin G (IgG) produced by peripheral blood mononuclear cells (PBMCs) from individuals exposed to P. falciparum or unexposed individuals. PBMCs, cultivated with or without cytokines and exogenous CD40/CD40L signals, were stimulated with a crude parasite extract, recombinant vaccine candidates derived from conserved Ags (19-kDa C terminus of merozoite surface protein 1 [MSP1 19 ], R23, and PfEB200), or recombinant Ags derived from the polymorphic Ags MSP1 block 2 and MSP2. No P. falciparum-specific Ab production was detected in PBMCs from unexposed individuals. PBMCs from donors exposed frequently to P. falciparum infections produced multiple IgG subclasses when they were stimulated with the parasite extract but usually only one IgG subclass when they were stimulated with a recombinant Ag. Optimal Ab production required addition of interleukin-2 (IL-2) and IL-10 for all antigenic preparations. The IgG subclass distribution was both donor and Ag dependent and was only minimally influenced by the exogenous cytokine environment. In vitro IgG production and subclass distribution correlated with plasma Abs to some Ags (MSP1 19 , R23, and MSP2) but not others (PfEB200 and the three MSP1 block 2-derived Ags). Data presented here suggest that intrinsic properties of the protein Ag itself play a major role in determining the subclass of the Ab response, which has important implications for rational design of vaccine delivery.1 Passive transfer of hyperimmune immunoglobulin G (IgG) to malaria patients has shown that antibodies (Abs) play a key role in protection against Plasmodium falciparum blood stages (12,25,30). In vitro studies have indicated that efficient parasite destruction is achieved through interaction of Abs with monocytes. Binding of Abs to an infected red blood cell results in opsonization of the infected cell (24), and Ab-dependent cellular inhibition of parasite growth is triggered by the binding of an IgG-merozoite complex to monocytes (5, 6, 40). Both mechanisms have been reported to involve IgG1 and IgG3 but not IgG2, which is normally noncytophilic (4, 8, 23). The efficiency of Ab-dependent cellular inhibition of parasite growth depends on the relative proportion of parasite-specific IgG1 and IgG3 compared to IgG2 (4). The data indicate that the subclass distribution of IgG Abs reacting with merozoite surface antigens (Ags) is an important parameter for protection against P. falciparum blood stages. In order to develop efficient blood stage vaccines, we need to better understand anti-P. falciparum IgG subclass production and/or switching.Identification of the parasite and host factors affecting Ab production by B cells might indicate ways in which vaccineinduced immune responses can be directed to ensure terminal differe...

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“…The results showed that some permutations of gain or loss of repeat motifs should influence the antigenicity. Other studies have also shown that antibodies react with diverse sequences in the K1-like repeats (10,18). Our aim was first to identify epitopes recognized by human antibodies and murine MAbs to the K1-like repeat sequences and then to design a minimal composite antigen sequence that would contain these epitopes.…”

Section: Discussionmentioning

confidence: 99%

Extensive Antigenic Polymorphism within the Repeat Sequence of thePlasmodium falciparumMerozoite Surface Protein 1 Block 2 Is Incorporated in a Minimal Polyvalent Immunogen

et al. 2005

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Polymorphism in pathogen antigens presents a complex challenge for vaccine design. A prime example is the N-terminal block 2 region of the Plasmodium falciparum merozoite surface protein 1 (MSP1), to which allele-specific antibodies have been associated with protection from malaria. In a Zambian population studied here, 49 of 91 alleles sampled were of the K1-like type (the most common of three block 2 types in all African populations), and most of these had unique sequences due to variation in tri-and hexapeptide repetitive motifs. There were significant negative correlations between allelic sequence lengths of different regions of the repeats, so the complete repeat sequence had less length variation than its component parts, suggesting a constraint on overall length. Diverse epitopes recognized by three murine monoclonal antibodies and 24 individual human sera were then mapped by using a comprehensive panel of synthetic peptides, revealing epitopes in all regions of the repeats. To incorporate these different epitopes in a single molecule, a composite sequence of minimal overall length (78 amino acids) was then designed and expressed as a recombinant antigen. More human immune sera reacted with this "K1-like Super Repeat" antigen than with proteins consisting of single natural allelic sequences, and immunization of mice elicited antibodies that recognized a range of five cultured parasite lines with diverse K1-like MSP1 block 2 repeat sequences. Thus, complex allelic polymorphism was deconstructed and a minimal composite polyvalent antigen was engineered, delivering a designed candidate sequence for inclusion in a malaria vaccine.

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Fixed, epitope-specific, cytophilic antibody response to the polymorphic block 2 domain of thePlasmodium falciparum merozoite surface antigen MSP-1 in humans living in a malaria-endemic area

Cited by 32 publications

References 30 publications

Antibodies to the N-Terminal Block 2 ofPlasmodium falciparumMerozoite Surface Protein 1 Are Associated with Protection against Clinical Malaria

Antibodies to the N-Terminal Block 2 ofPlasmodium falciparumMerozoite Surface Protein 1 Are Associated with Protection against Clinical Malaria

Regulation of Antigen-Specific Immunoglobulin G Subclasses in Response to Conserved and PolymorphicPlasmodium falciparumAntigens in an In Vitro Model

Extensive Antigenic Polymorphism within the Repeat Sequence of thePlasmodium falciparumMerozoite Surface Protein 1 Block 2 Is Incorporated in a Minimal Polyvalent Immunogen

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