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Evaluation of Plasmodium vivax Cell-Traversal Protein for Ookinetes and Sporozoites as a Preerythrocytic P. vivax Vaccine

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ABSTRACT

Four different vaccine platforms, each targeting the human malaria parasite Plasmodium vivax cell-traversal protein for ookinetes and sporozoites (PvCelTOS), were generated and assessed for protective efficacy. These platforms consisted of a recombinant chimpanzee adenoviral vector 63 (ChAd63) expressing PvCelTOS (Ad), a recombinant modified vaccinia virus Ankara expressing PvCelTOS (MVA), PvCelTOS conjugated to bacteriophage Qβ virus-like particles (VLPs), and a recombinant PvCelTOS protein expressed in eukaryotic HEK293T cells (protein). Inbred BALB/c mice and outbred CD-1 mice were immunized using the following prime-boost regimens: Ad-MVA, Ad-VLPs, and Ad-protein. Protective efficacy against sporozoite challenge was assessed after immunization using a novel chimeric rodent Plasmodium berghei parasite (Pb-PvCelTOS). This chimeric parasite expresses P. vivax CelTOS in place of the endogenous P. berghei CelTOS and produces fully infectious sporozoites. A single Ad immunization in BALB/c and CD-1 mice induced anti-PvCelTOS antibodies which were boosted efficiently using MVA, VLP, or protein immunization. PvCelTOS-specific gamma interferon- and tumor necrosis factor alpha-producing CD8+ T cells were induced at high frequencies by all prime-boost regimens in BALB/c mice but not in CD-1 mice; in CD-1 mice, they were only marginally increased after boosting with MVA. Despite the induction of anti-PvCelTOS antibodies and PvCelTOS-specific CD8+ T-cell responses, only low levels of protective efficacy against challenge with Pb-PvCelTOS sporozoites were obtained using any immunization strategy. In BALB/c mice, no immunization regimens provided significant protection against a Pb-PvCelTOS chimeric sporozoite challenge. In CD-1 mice, modest protective efficacy against challenge with chimeric P. berghei sporozoites expressing either PvCelTOS or P. falciparum CelTOS was observed using the Ad-protein vaccination regimen.

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Vaccination regimens and induction of antibody responses against P. vivax CelTOS in outbred CD-1 and inbred BALB/c mice. (A) Flowchart of the vaccination regimens used in this study. Three groups of 6 mice each were primed with the viral ChAd63 vector (Ad) expressing PvCelTOS (ChAd63-PvCelTOS). These groups were subsequently boosted with (i) the MVA viral vector expressing PvCelTOS (MVA-PvCelTOS), (ii) the PvCelTOS protein expressed in eukaryotic HEK293T cells (PvCelTOS), or (iii) the PvCelTOS protein conjugated to bacteriophage Qβ VLPs (VLP-PvCelTOS). Blood samples were collected at 14 days after the Ad prime and at day 63 after the boost. (B) Endpoint titer ELISA showing the total IgG antibody response against recombinant PvCelTOS protein in CD-1 mice after priming with Ad (day 14) or after boosting with MVA, protein, or VLPs (day 63), as shown in panel A. Means with standard errors of the means (SEMs) are shown. P values were determined by Tukey's multiple-comparison test. *, P < 0.05; ****, P < 0.0001. (C) Endpoint titer ELISA showing the total IgG antibody response against recombinant PvCelTOS protein in BALB/c mice after priming with Ad (day 14) or after boosting with MVA, protein, or VLPs (day 63), as shown in panel A. Means with SEMs are shown. P values were determined by Tukey's multiple-comparison test. **, P < 0.01; ****, P < 0.0001.
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Figure 1: Vaccination regimens and induction of antibody responses against P. vivax CelTOS in outbred CD-1 and inbred BALB/c mice. (A) Flowchart of the vaccination regimens used in this study. Three groups of 6 mice each were primed with the viral ChAd63 vector (Ad) expressing PvCelTOS (ChAd63-PvCelTOS). These groups were subsequently boosted with (i) the MVA viral vector expressing PvCelTOS (MVA-PvCelTOS), (ii) the PvCelTOS protein expressed in eukaryotic HEK293T cells (PvCelTOS), or (iii) the PvCelTOS protein conjugated to bacteriophage Qβ VLPs (VLP-PvCelTOS). Blood samples were collected at 14 days after the Ad prime and at day 63 after the boost. (B) Endpoint titer ELISA showing the total IgG antibody response against recombinant PvCelTOS protein in CD-1 mice after priming with Ad (day 14) or after boosting with MVA, protein, or VLPs (day 63), as shown in panel A. Means with standard errors of the means (SEMs) are shown. P values were determined by Tukey's multiple-comparison test. *, P < 0.05; ****, P < 0.0001. (C) Endpoint titer ELISA showing the total IgG antibody response against recombinant PvCelTOS protein in BALB/c mice after priming with Ad (day 14) or after boosting with MVA, protein, or VLPs (day 63), as shown in panel A. Means with SEMs are shown. P values were determined by Tukey's multiple-comparison test. **, P < 0.01; ****, P < 0.0001.

Mentions: We developed four vaccine platforms to induce immune responses directed against PvCelTOS: a recombinant chimpanzee adenoviral vector (ChAd63) expressing PvCelTOS (Ad), a recombinant MVA vector expressing PvCelTOS (MVA), PvCelTOS conjugated to bacteriophage Qβ virus-like particles (VLPs), and the PvCelTOS protein produced in eukaryotic HEK293T cells (protein). VLPs and protein were delivered using the Matrix-M adjuvant. To prime immune responses in BALB/c and CD-1 mice, ChAd63-PvCelTOS was injected intramuscularly. The other three vaccine platforms were injected intramuscularly 8 weeks later to boost responses, such that three groups of mice (n = 6 each) were immunized with the following: Ad-MVA, Ad-protein, and Ad-VLPs (Fig. 1A). Serum and peripheral blood mononuclear cells (PBMCs) were collected 7 days after priming and after boosting to assess the humoral and cellular immune responses. We followed this prime-boost approach using a chimpanzee adenovirus followed by other platforms, as it has previously been described that an initial adenovirus prime can benefit subsequent boosting immunizations, as well as support the induction of T effector memory (Tem) cells that correlate with protection upon a sporozoite challenge (31, 32).


Evaluation of Plasmodium vivax Cell-Traversal Protein for Ookinetes and Sporozoites as a Preerythrocytic P. vivax Vaccine
Vaccination regimens and induction of antibody responses against P. vivax CelTOS in outbred CD-1 and inbred BALB/c mice. (A) Flowchart of the vaccination regimens used in this study. Three groups of 6 mice each were primed with the viral ChAd63 vector (Ad) expressing PvCelTOS (ChAd63-PvCelTOS). These groups were subsequently boosted with (i) the MVA viral vector expressing PvCelTOS (MVA-PvCelTOS), (ii) the PvCelTOS protein expressed in eukaryotic HEK293T cells (PvCelTOS), or (iii) the PvCelTOS protein conjugated to bacteriophage Qβ VLPs (VLP-PvCelTOS). Blood samples were collected at 14 days after the Ad prime and at day 63 after the boost. (B) Endpoint titer ELISA showing the total IgG antibody response against recombinant PvCelTOS protein in CD-1 mice after priming with Ad (day 14) or after boosting with MVA, protein, or VLPs (day 63), as shown in panel A. Means with standard errors of the means (SEMs) are shown. P values were determined by Tukey's multiple-comparison test. *, P < 0.05; ****, P < 0.0001. (C) Endpoint titer ELISA showing the total IgG antibody response against recombinant PvCelTOS protein in BALB/c mice after priming with Ad (day 14) or after boosting with MVA, protein, or VLPs (day 63), as shown in panel A. Means with SEMs are shown. P values were determined by Tukey's multiple-comparison test. **, P < 0.01; ****, P < 0.0001.
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Figure 1: Vaccination regimens and induction of antibody responses against P. vivax CelTOS in outbred CD-1 and inbred BALB/c mice. (A) Flowchart of the vaccination regimens used in this study. Three groups of 6 mice each were primed with the viral ChAd63 vector (Ad) expressing PvCelTOS (ChAd63-PvCelTOS). These groups were subsequently boosted with (i) the MVA viral vector expressing PvCelTOS (MVA-PvCelTOS), (ii) the PvCelTOS protein expressed in eukaryotic HEK293T cells (PvCelTOS), or (iii) the PvCelTOS protein conjugated to bacteriophage Qβ VLPs (VLP-PvCelTOS). Blood samples were collected at 14 days after the Ad prime and at day 63 after the boost. (B) Endpoint titer ELISA showing the total IgG antibody response against recombinant PvCelTOS protein in CD-1 mice after priming with Ad (day 14) or after boosting with MVA, protein, or VLPs (day 63), as shown in panel A. Means with standard errors of the means (SEMs) are shown. P values were determined by Tukey's multiple-comparison test. *, P < 0.05; ****, P < 0.0001. (C) Endpoint titer ELISA showing the total IgG antibody response against recombinant PvCelTOS protein in BALB/c mice after priming with Ad (day 14) or after boosting with MVA, protein, or VLPs (day 63), as shown in panel A. Means with SEMs are shown. P values were determined by Tukey's multiple-comparison test. **, P < 0.01; ****, P < 0.0001.
Mentions: We developed four vaccine platforms to induce immune responses directed against PvCelTOS: a recombinant chimpanzee adenoviral vector (ChAd63) expressing PvCelTOS (Ad), a recombinant MVA vector expressing PvCelTOS (MVA), PvCelTOS conjugated to bacteriophage Qβ virus-like particles (VLPs), and the PvCelTOS protein produced in eukaryotic HEK293T cells (protein). VLPs and protein were delivered using the Matrix-M adjuvant. To prime immune responses in BALB/c and CD-1 mice, ChAd63-PvCelTOS was injected intramuscularly. The other three vaccine platforms were injected intramuscularly 8 weeks later to boost responses, such that three groups of mice (n = 6 each) were immunized with the following: Ad-MVA, Ad-protein, and Ad-VLPs (Fig. 1A). Serum and peripheral blood mononuclear cells (PBMCs) were collected 7 days after priming and after boosting to assess the humoral and cellular immune responses. We followed this prime-boost approach using a chimpanzee adenovirus followed by other platforms, as it has previously been described that an initial adenovirus prime can benefit subsequent boosting immunizations, as well as support the induction of T effector memory (Tem) cells that correlate with protection upon a sporozoite challenge (31, 32).

View Article: PubMed Central - PubMed

ABSTRACT

Four different vaccine platforms, each targeting the human malaria parasite Plasmodium vivax cell-traversal protein for ookinetes and sporozoites (PvCelTOS), were generated and assessed for protective efficacy. These platforms consisted of a recombinant chimpanzee adenoviral vector 63 (ChAd63) expressing PvCelTOS (Ad), a recombinant modified vaccinia virus Ankara expressing PvCelTOS (MVA), PvCelTOS conjugated to bacteriophage Q&beta; virus-like particles (VLPs), and a recombinant PvCelTOS protein expressed in eukaryotic HEK293T cells (protein). Inbred BALB/c mice and outbred CD-1 mice were immunized using the following prime-boost regimens: Ad-MVA, Ad-VLPs, and Ad-protein. Protective efficacy against sporozoite challenge was assessed after immunization using a novel chimeric rodent Plasmodium berghei parasite (Pb-PvCelTOS). This chimeric parasite expresses P. vivax CelTOS in place of the endogenous P. berghei CelTOS and produces fully infectious sporozoites. A single Ad immunization in BALB/c and CD-1 mice induced anti-PvCelTOS antibodies which were boosted efficiently using MVA, VLP, or protein immunization. PvCelTOS-specific gamma interferon- and tumor necrosis factor alpha-producing CD8+ T cells were induced at high frequencies by all prime-boost regimens in BALB/c mice but not in CD-1 mice; in CD-1 mice, they were only marginally increased after boosting with MVA. Despite the induction of anti-PvCelTOS antibodies and PvCelTOS-specific CD8+ T-cell responses, only low levels of protective efficacy against challenge with Pb-PvCelTOS sporozoites were obtained using any immunization strategy. In BALB/c mice, no immunization regimens provided significant protection against a Pb-PvCelTOS chimeric sporozoite challenge. In CD-1 mice, modest protective efficacy against challenge with chimeric P. berghei sporozoites expressing either PvCelTOS or P. falciparum CelTOS was observed using the Ad-protein vaccination regimen.

No MeSH data available.


Related in: MedlinePlus