Plasmodium falciparum:gp195 Tripeptide Repeat-Specific Monoclonal Antibody Inhibits Parasite Growthin Vitro

Locher, Christopher P.; Tam, Leslie Q.; Chang, Sandra P.; McBride, Jana S.; Siddiqui, Wasim A.

doi:10.1006/expr.1996.0091

Cited by 28 publications

(24 citation statements)

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“…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. MAbs recognized single deduced epitopes, with specificity consistent with expectations from previous studies with native and recombinant antigens (5,24). Sera from Nigerian and Gambian adults each recognized between one and three deduced epitopes (a few had weaker additional reactivities that were not resolved).…”

Section: Discussionsupporting

confidence: 84%

“…Antigens of P. falciparum that appear to be under such selection include the merozoite apical membrane antigen 1 (AMA1) (30,31) and the merozoite surface proteins 1 (MSP1) (7) and MSP2 (6). For each of these antigens, there is also evidence from epidemiological studies or in vitro parasite inhibition assays that allele-specific antibodies have a protective effect (1,7,15,19,21,24,26,27,34).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 84%

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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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“…For example, recombinant fusion proteins prepared from the tandem repeats in VAR I of PbMSP-1 protected equally well against P. berghei challenge as fusion proteins lacking the repeats or fusion proteins containing both the non-repeat and repeat regions [55]. Similarly, a mAb against the tri-peptide repeats in variable block 2 of PfMSP-1 inhibits the in vitro growth of P. falciparum [33]. The predominant amino acids in the variable blocks are uncharged amino acids of intermediate hydrophobicity.…”

Section: Discussionmentioning

confidence: 99%

The complete sequence of Plasmodium berghei merozoite surface protein-1 and its inter- and intra-species variability

Jennings

Toebe

Belkum

et al. 1998

Molecular and Biochemical Parasitology

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The complete gene for merozoite surface protein-1 (MSP-1) from Plasmodium berghei has been cloned and sequenced. Comparison of the P. berghei MSP-1 sequence with MSP-1 from other rodent parasites reveals five conserved domains interrupted by four variable blocks. These variable blocks exhibit no sequence homology but do have similar amino acid compositions. Primary proteolytic processing sites are located near the boundaries between the conserved domains and the variable blocks. Sequencing of the variable blocks from several P. berghei isolates shows that the predominant intra-species difference is in the number of tandem repeats. The inter-and intra-species differences suggest that the variable blocks are localized areas with relatively high levels of slipped-strand mispairing, unequal crossing-over, or other intragenic recombination activity. MSP-1 from P. berghei exhibits more repetitiveness than MSP-1 from other species suggesting that P. berghei experiences a higher intrinsic level of events producing variable numbers of tandem repeats or a lower level of events leading to the degeneration of tandem repeats.

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“…Similar immunization experiments in rodents also generated high levels of protection (20). Moreover, monoclonal antibodies and antisera specific for the antigen can also inhibit parasite growth both in vitro and in vivo (17,26,30). The MSP1 gene, however, is highly unstable in E. coli due to its unusually high AϩT content, which renders cloning of the full-length gene impossible (39).…”

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confidence: 90%

Construction of atetR-IntegratedSalmonella entericaSerovar Typhi CVD908 Strain That Tightly Controls Expression of the Major Merozoite Surface Protein ofPlasmodium falciparumfor Applications in Human Vaccine Production

Qian

2002

Infect Immun

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Attenuated Salmonella strains are an attractive live vector for delivery of a foreign antigen to the human immune system. However, the problem with this vector lies with plasmid segregation and the low level of expression of the foreign gene in vivo when constitutive expression is employed, leading to a diminished immune response. We have established inducible expressions of foreign genes in the Salmonella enterica serovar Typhi CVD908 vaccine strain using the tetracycline response regulatory promoter. To set up this system, a tetracycline repressor (tetR) was integrated into a defined ⌬aroC locus of the chromosome via suicide plasmid pJG12/tetR-neo. To remove the neo gene conferring kanamycin resistance from the locus, a cre expression vector under the control of the tetracycline response promoter was transformed into the clone; expression of the Cre recombinase excised the neo gene and generated the end strain CVD908-tetR. Expression of the luciferase reporter gene in this strain is dependent on the presence of tetracycline in the medium and can be regulated up to 4,773-fold. Moreover, the tightly controlled expression of major merozoite surface protein 1 (MSP1) and parts of Plasmodium falciparum was achieved, and the product yield was increased when the inducible expression system was employed. Inoculation of bacteria harboring plasmid pZE11/MSP1 42 in mice produced the protein in liver and spleen controlled by the inducer. The persistence of the plasmid-carrying bacteria in mice was determined. Peak colonization of both liver and spleen was detected on the third day postinoculation and was followed by a decline in growth curves. After 14 days postinfection, the majority of the bacteria (>90%) recovered from the liver and spleen of the mice retained the plasmid when expression was induced; this clearly indicated that stability of the expression vector in vivo was improved by inducible expression. Establishment of the regulatory system in the vaccine strain may broaden the range of its use by enhancing plasmid stability and expression levels in vivo. Moreover, the availability of the vaccine strain inducibly expressing the entire MSP1 provides possibilities for examining its immunogenicity, particularly the cellular response in animal models.

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Plasmodium falciparum:gp195 Tripeptide Repeat-Specific Monoclonal Antibody Inhibits Parasite Growthin Vitro

Cited by 28 publications

References 0 publications

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

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

The complete sequence of Plasmodium berghei merozoite surface protein-1 and its inter- and intra-species variability

Construction of atetR-IntegratedSalmonella entericaSerovar Typhi CVD908 Strain That Tightly Controls Expression of the Major Merozoite Surface Protein ofPlasmodium falciparumfor Applications in Human Vaccine Production

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