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Plasmodium berghei circumvents immune responses induced by merozoite surface protein 1- and apical membrane antigen 1-based vaccines.

Yoshida S, Nagumo H, Yokomine T, Araki H, Suzuki A, Matsuoka H - PLoS ONE (2010)

Bottom Line: Similarly, neither P. berghei MSP1(19)- nor AMA1-BBV was effective against P. berghei.P. berghei completely circumvents immune responses induced by MSP1(19)- and AMA1-based vaccines, suggesting that P. berghei possesses additional molecules and/or mechanisms that circumvent the host's immune responses to MSP1(19) and AMA1, which are lacking in P. yoelii.Although it is not known whether P. falciparum shares these escape mechanisms with P. berghei, P. berghei and its transgenic models may have potential as useful tools for identifying and evaluating new blood-stage vaccine candidate antigens for P. falciparum.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Zoology, Department of Infection and Immunity, Jichi Medical University, Tochigi, Japan. shigeto@p.kanazawa-u.ac.jp

ABSTRACT

Background: Two current leading malaria blood-stage vaccine candidate antigens for Plasmodium falciparum, the C-terminal region of merozoite surface protein 1 (MSP1(19)) and apical membrane antigen 1 (AMA1), have been prioritized because of outstanding protective efficacies achieved in a rodent malaria Plasmodium yoelii model. However, P. falciparum vaccines based on these antigens have had disappointing outcomes in clinical trials. Discrepancies in the vaccine efficacies observed between the P. yoelii model and human clinical trials still remain problematic.

Methodology and results: In this study, we assessed the protective efficacies of a series of MSP1(19)- and AMA1-based vaccines using the P. berghei rodent malarial parasite and its transgenic models. Immunization of mice with a baculoviral-based vaccine (BBV) expressing P. falciparum MSP1(19) induced high titers of PfMSP1(19)-specific antibodies that strongly reacted with P. falciparum blood-stage parasites. However, no protection was achieved following lethal challenge with transgenic P. berghei expressing PfMSP1(19) in place of native PbMSP1(19). Similarly, neither P. berghei MSP1(19)- nor AMA1-BBV was effective against P. berghei. In contrast, immunization with P. yoelii MSP1(19)- and AMA1-BBVs provided 100% and 40% protection, respectively, against P. yoelii lethal challenge. Mice that naturally acquired sterile immunity against P. berghei became cross-resistant to P. yoelii, but not vice versa.

Conclusion: This is the first study to address blood-stage vaccine efficacies using both P. berghei and P. yoelii models at the same time. P. berghei completely circumvents immune responses induced by MSP1(19)- and AMA1-based vaccines, suggesting that P. berghei possesses additional molecules and/or mechanisms that circumvent the host's immune responses to MSP1(19) and AMA1, which are lacking in P. yoelii. Although it is not known whether P. falciparum shares these escape mechanisms with P. berghei, P. berghei and its transgenic models may have potential as useful tools for identifying and evaluating new blood-stage vaccine candidate antigens for P. falciparum.

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Construction and expression analysis of AMA1-BBVs.(A) Schematic diagram of four AMA1-BBV genomes. AMA1 was expressed as an AMA1-gp64 fusion protein under the control of the polyhedron promoter. Numbers indicate the amino acid positions of AMA1-gp64 fusion protein and endogenous gp64 protein. pPolh, polyhedrin promoter; SP, the gp64 signal sequence; FLAG, the FLAG epitope tag; pgp64, gp64 promoter. (B) Western blot analysis of AMA1-BBVs. AcNPV-PyAMA1-D123surf (lane 1), AcNPV-PyAMA1-D3surf (lane 2), AcNPV-PbAMA1-D123surf (lane 3) and AcNPV-PbAMA1-D3surf (lane 4) were treated with the loading buffer containing 1% 2-ME and examined using P. yoelii-hyperimmune serum (lanes 1 and 2), or P. berghei-hyperimmune serum (lanes 3 and 4). (C–J) Immunofluorescence patterns of sera obtained from mice immunized with four AMA1-BBVs on methanol-acetone fixed smears of erythrocytes infected with P. yoelii (C and E) and P. berghei (G and I). The smears were incubated with serum obtained from an individual mouse immunized either with AcNPV-PyAMA1-D123surf (C), AcNPV-PyAMA1-D3surf (E), AcNPV-PbAMA1-D123surf (G) or AcNPV-PbAMA1-D3surf (I), and antibody binding was detected with a secondary FITC-labeled antibody. Cell nuclei were visualized by DAPI staining on the corresponding smears (D, F, H and J). Scale bar, 10 µm.
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pone-0013727-g003: Construction and expression analysis of AMA1-BBVs.(A) Schematic diagram of four AMA1-BBV genomes. AMA1 was expressed as an AMA1-gp64 fusion protein under the control of the polyhedron promoter. Numbers indicate the amino acid positions of AMA1-gp64 fusion protein and endogenous gp64 protein. pPolh, polyhedrin promoter; SP, the gp64 signal sequence; FLAG, the FLAG epitope tag; pgp64, gp64 promoter. (B) Western blot analysis of AMA1-BBVs. AcNPV-PyAMA1-D123surf (lane 1), AcNPV-PyAMA1-D3surf (lane 2), AcNPV-PbAMA1-D123surf (lane 3) and AcNPV-PbAMA1-D3surf (lane 4) were treated with the loading buffer containing 1% 2-ME and examined using P. yoelii-hyperimmune serum (lanes 1 and 2), or P. berghei-hyperimmune serum (lanes 3 and 4). (C–J) Immunofluorescence patterns of sera obtained from mice immunized with four AMA1-BBVs on methanol-acetone fixed smears of erythrocytes infected with P. yoelii (C and E) and P. berghei (G and I). The smears were incubated with serum obtained from an individual mouse immunized either with AcNPV-PyAMA1-D123surf (C), AcNPV-PyAMA1-D3surf (E), AcNPV-PbAMA1-D123surf (G) or AcNPV-PbAMA1-D3surf (I), and antibody binding was detected with a secondary FITC-labeled antibody. Cell nuclei were visualized by DAPI staining on the corresponding smears (D, F, H and J). Scale bar, 10 µm.

Mentions: To compare the protective efficacies of another leading vaccine candidate, AMA1, against P. yoelii and P. berghei, we generated two kinds of PyAMA1- and PbAMA1-BBVs consisting of ectodomains I-III or III alone (AcNPV-PyAMA1-D123surf, AcNPV-PyAMA1-D3surf, AcNPV-PbAMA1-D123suf, and AcNPV-PbAMA1-D3surf) (Figure 3A). Similar to MSP119-BBV, each construct harbored a gene cassette that consisted of the gp64 signal sequence and the target gene (PyAMA1-D123, PyAMA1-D3, PbAMA1-D123, and PbAMA1-D3) fused to the N-terminus of the AcNPV major envelope protein gp64. Western blotting analysis shows that P. yoelii-hyperimmune serum reacted with the PyAMA1-D123- and PyAMA1-D3-gp64 fusion proteins of AcNPV-PyAMA1-D123suf and AcNPV-PyAMA1-D3surf with molecular weights of 125 kDa and 95 kDa, respectively (Figure 3B, lanes 1 and 2). Similar results were obtained with the PbAMA1-D123- and PbAMA1-D3-gp64 fusion proteins of AcNPV-PbAMA1-D123suf and AcNPV-PbAMA1-D3surf against P. berghei-hyperimmune serum (lanes 3 and 4).


Plasmodium berghei circumvents immune responses induced by merozoite surface protein 1- and apical membrane antigen 1-based vaccines.

Yoshida S, Nagumo H, Yokomine T, Araki H, Suzuki A, Matsuoka H - PLoS ONE (2010)

Construction and expression analysis of AMA1-BBVs.(A) Schematic diagram of four AMA1-BBV genomes. AMA1 was expressed as an AMA1-gp64 fusion protein under the control of the polyhedron promoter. Numbers indicate the amino acid positions of AMA1-gp64 fusion protein and endogenous gp64 protein. pPolh, polyhedrin promoter; SP, the gp64 signal sequence; FLAG, the FLAG epitope tag; pgp64, gp64 promoter. (B) Western blot analysis of AMA1-BBVs. AcNPV-PyAMA1-D123surf (lane 1), AcNPV-PyAMA1-D3surf (lane 2), AcNPV-PbAMA1-D123surf (lane 3) and AcNPV-PbAMA1-D3surf (lane 4) were treated with the loading buffer containing 1% 2-ME and examined using P. yoelii-hyperimmune serum (lanes 1 and 2), or P. berghei-hyperimmune serum (lanes 3 and 4). (C–J) Immunofluorescence patterns of sera obtained from mice immunized with four AMA1-BBVs on methanol-acetone fixed smears of erythrocytes infected with P. yoelii (C and E) and P. berghei (G and I). The smears were incubated with serum obtained from an individual mouse immunized either with AcNPV-PyAMA1-D123surf (C), AcNPV-PyAMA1-D3surf (E), AcNPV-PbAMA1-D123surf (G) or AcNPV-PbAMA1-D3surf (I), and antibody binding was detected with a secondary FITC-labeled antibody. Cell nuclei were visualized by DAPI staining on the corresponding smears (D, F, H and J). Scale bar, 10 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2965677&req=5

pone-0013727-g003: Construction and expression analysis of AMA1-BBVs.(A) Schematic diagram of four AMA1-BBV genomes. AMA1 was expressed as an AMA1-gp64 fusion protein under the control of the polyhedron promoter. Numbers indicate the amino acid positions of AMA1-gp64 fusion protein and endogenous gp64 protein. pPolh, polyhedrin promoter; SP, the gp64 signal sequence; FLAG, the FLAG epitope tag; pgp64, gp64 promoter. (B) Western blot analysis of AMA1-BBVs. AcNPV-PyAMA1-D123surf (lane 1), AcNPV-PyAMA1-D3surf (lane 2), AcNPV-PbAMA1-D123surf (lane 3) and AcNPV-PbAMA1-D3surf (lane 4) were treated with the loading buffer containing 1% 2-ME and examined using P. yoelii-hyperimmune serum (lanes 1 and 2), or P. berghei-hyperimmune serum (lanes 3 and 4). (C–J) Immunofluorescence patterns of sera obtained from mice immunized with four AMA1-BBVs on methanol-acetone fixed smears of erythrocytes infected with P. yoelii (C and E) and P. berghei (G and I). The smears were incubated with serum obtained from an individual mouse immunized either with AcNPV-PyAMA1-D123surf (C), AcNPV-PyAMA1-D3surf (E), AcNPV-PbAMA1-D123surf (G) or AcNPV-PbAMA1-D3surf (I), and antibody binding was detected with a secondary FITC-labeled antibody. Cell nuclei were visualized by DAPI staining on the corresponding smears (D, F, H and J). Scale bar, 10 µm.
Mentions: To compare the protective efficacies of another leading vaccine candidate, AMA1, against P. yoelii and P. berghei, we generated two kinds of PyAMA1- and PbAMA1-BBVs consisting of ectodomains I-III or III alone (AcNPV-PyAMA1-D123surf, AcNPV-PyAMA1-D3surf, AcNPV-PbAMA1-D123suf, and AcNPV-PbAMA1-D3surf) (Figure 3A). Similar to MSP119-BBV, each construct harbored a gene cassette that consisted of the gp64 signal sequence and the target gene (PyAMA1-D123, PyAMA1-D3, PbAMA1-D123, and PbAMA1-D3) fused to the N-terminus of the AcNPV major envelope protein gp64. Western blotting analysis shows that P. yoelii-hyperimmune serum reacted with the PyAMA1-D123- and PyAMA1-D3-gp64 fusion proteins of AcNPV-PyAMA1-D123suf and AcNPV-PyAMA1-D3surf with molecular weights of 125 kDa and 95 kDa, respectively (Figure 3B, lanes 1 and 2). Similar results were obtained with the PbAMA1-D123- and PbAMA1-D3-gp64 fusion proteins of AcNPV-PbAMA1-D123suf and AcNPV-PbAMA1-D3surf against P. berghei-hyperimmune serum (lanes 3 and 4).

Bottom Line: Similarly, neither P. berghei MSP1(19)- nor AMA1-BBV was effective against P. berghei.P. berghei completely circumvents immune responses induced by MSP1(19)- and AMA1-based vaccines, suggesting that P. berghei possesses additional molecules and/or mechanisms that circumvent the host's immune responses to MSP1(19) and AMA1, which are lacking in P. yoelii.Although it is not known whether P. falciparum shares these escape mechanisms with P. berghei, P. berghei and its transgenic models may have potential as useful tools for identifying and evaluating new blood-stage vaccine candidate antigens for P. falciparum.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Zoology, Department of Infection and Immunity, Jichi Medical University, Tochigi, Japan. shigeto@p.kanazawa-u.ac.jp

ABSTRACT

Background: Two current leading malaria blood-stage vaccine candidate antigens for Plasmodium falciparum, the C-terminal region of merozoite surface protein 1 (MSP1(19)) and apical membrane antigen 1 (AMA1), have been prioritized because of outstanding protective efficacies achieved in a rodent malaria Plasmodium yoelii model. However, P. falciparum vaccines based on these antigens have had disappointing outcomes in clinical trials. Discrepancies in the vaccine efficacies observed between the P. yoelii model and human clinical trials still remain problematic.

Methodology and results: In this study, we assessed the protective efficacies of a series of MSP1(19)- and AMA1-based vaccines using the P. berghei rodent malarial parasite and its transgenic models. Immunization of mice with a baculoviral-based vaccine (BBV) expressing P. falciparum MSP1(19) induced high titers of PfMSP1(19)-specific antibodies that strongly reacted with P. falciparum blood-stage parasites. However, no protection was achieved following lethal challenge with transgenic P. berghei expressing PfMSP1(19) in place of native PbMSP1(19). Similarly, neither P. berghei MSP1(19)- nor AMA1-BBV was effective against P. berghei. In contrast, immunization with P. yoelii MSP1(19)- and AMA1-BBVs provided 100% and 40% protection, respectively, against P. yoelii lethal challenge. Mice that naturally acquired sterile immunity against P. berghei became cross-resistant to P. yoelii, but not vice versa.

Conclusion: This is the first study to address blood-stage vaccine efficacies using both P. berghei and P. yoelii models at the same time. P. berghei completely circumvents immune responses induced by MSP1(19)- and AMA1-based vaccines, suggesting that P. berghei possesses additional molecules and/or mechanisms that circumvent the host's immune responses to MSP1(19) and AMA1, which are lacking in P. yoelii. Although it is not known whether P. falciparum shares these escape mechanisms with P. berghei, P. berghei and its transgenic models may have potential as useful tools for identifying and evaluating new blood-stage vaccine candidate antigens for P. falciparum.

Show MeSH
Related in: MedlinePlus