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Efficacy of a Plasmodium vivax malaria vaccine using ChAd63 and modified vaccinia Ankara expressing thrombospondin-related anonymous protein as assessed with transgenic Plasmodium berghei parasites.

Bauza K, Malinauskas T, Pfander C, Anar B, Jones EY, Billker O, Hill AV, Reyes-Sandoval A - Infect. Immun. (2013)

Bottom Line: Plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America.Using this model, we found that both CD8+ T cells and antibodies mediated protection against malaria using virus-vectored vaccines.Our data indicate that ChAd63 and MVA expressing PvTRAP are good preerythrocytic-stage vaccine candidates with potential for future clinical application.

View Article: PubMed Central - PubMed

Affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America. Despite this dramatic burden, very few vaccines have been assessed in humans. The clinically relevant vectors modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAd63 are promising delivery systems for malaria vaccines due to their safety profiles and proven ability to induce protective immune responses against Plasmodium falciparum thrombospondin-related anonymous protein (TRAP) in clinical trials. Here, we describe the development of new recombinant ChAd63 and MVA vectors expressing P. vivax TRAP (PvTRAP) and show their ability to induce high antibody titers and T cell responses in mice. In addition, we report a novel way of assessing the efficacy of new candidate vaccines against P. vivax using a fully infectious transgenic Plasmodium berghei parasite expressing P. vivax TRAP to allow studies of vaccine efficacy and protective mechanisms in rodents. Using this model, we found that both CD8+ T cells and antibodies mediated protection against malaria using virus-vectored vaccines. Our data indicate that ChAd63 and MVA expressing PvTRAP are good preerythrocytic-stage vaccine candidates with potential for future clinical application.

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Protection against sporozoite challenge is mediated by both PvTRAP-specific CD8+ T cells and antibodies. (a) Flow cytometry analysis of PBMCs from mice, indicating that injection of anti-GK1.5 or anti-2.43 was approximately 99% effective at depleting CD4+ or CD8+ cells, respectively. rlgG1 MAb served as a negative control. (b and c) Effect of depletion of CD4+ or CD8+ T cells on protection against parasite challenge. BALB/c and CD1 mice (n = 12) were first vaccinated using a heterologous prime-boost regimen with Ad-MVA expressing PvTRAP. Two weeks after the final vaccination, the mice received depleting anti-GK1.5 or anti-2.43 antibodies on days −2, −1, and 0 relative to the challenge. P values were generated using a Kaplan-Meyer method to compare survival curves. n.s., not significant. (d) Survival curve of CD1 mice upon PvTRAP antibody transfer. Two weeks after the last vaccination, whole IgG was purified from serum, and 2 mg was transferred to naive CD1 mice (PvTRAP IgG). Whole IgG raised against empty viral vectors was also included (control IgG).
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Figure 5: Protection against sporozoite challenge is mediated by both PvTRAP-specific CD8+ T cells and antibodies. (a) Flow cytometry analysis of PBMCs from mice, indicating that injection of anti-GK1.5 or anti-2.43 was approximately 99% effective at depleting CD4+ or CD8+ cells, respectively. rlgG1 MAb served as a negative control. (b and c) Effect of depletion of CD4+ or CD8+ T cells on protection against parasite challenge. BALB/c and CD1 mice (n = 12) were first vaccinated using a heterologous prime-boost regimen with Ad-MVA expressing PvTRAP. Two weeks after the final vaccination, the mice received depleting anti-GK1.5 or anti-2.43 antibodies on days −2, −1, and 0 relative to the challenge. P values were generated using a Kaplan-Meyer method to compare survival curves. n.s., not significant. (d) Survival curve of CD1 mice upon PvTRAP antibody transfer. Two weeks after the last vaccination, whole IgG was purified from serum, and 2 mg was transferred to naive CD1 mice (PvTRAP IgG). Whole IgG raised against empty viral vectors was also included (control IgG).

Mentions: We further investigated the immune mechanisms associated with protection in a PvTRAP transgenic sporozoite challenge. CD4+ or CD8+ T cells were depleted by administration of the monoclonal antibody GK1.5, which binds to the CD4+ molecule, or the monoclonal antibody 2.43, which binds to the CD8+ molecule, both of which induce the depletion in blood of cells bearing these coreceptors (Fig. 5a). Antibodies were administered on three consecutive days after a boosting vaccine with MVA-PvTRAP, which corresponded to days −2, −1, and 0 with respect to the time of the sporozoite challenge.


Efficacy of a Plasmodium vivax malaria vaccine using ChAd63 and modified vaccinia Ankara expressing thrombospondin-related anonymous protein as assessed with transgenic Plasmodium berghei parasites.

Bauza K, Malinauskas T, Pfander C, Anar B, Jones EY, Billker O, Hill AV, Reyes-Sandoval A - Infect. Immun. (2013)

Protection against sporozoite challenge is mediated by both PvTRAP-specific CD8+ T cells and antibodies. (a) Flow cytometry analysis of PBMCs from mice, indicating that injection of anti-GK1.5 or anti-2.43 was approximately 99% effective at depleting CD4+ or CD8+ cells, respectively. rlgG1 MAb served as a negative control. (b and c) Effect of depletion of CD4+ or CD8+ T cells on protection against parasite challenge. BALB/c and CD1 mice (n = 12) were first vaccinated using a heterologous prime-boost regimen with Ad-MVA expressing PvTRAP. Two weeks after the final vaccination, the mice received depleting anti-GK1.5 or anti-2.43 antibodies on days −2, −1, and 0 relative to the challenge. P values were generated using a Kaplan-Meyer method to compare survival curves. n.s., not significant. (d) Survival curve of CD1 mice upon PvTRAP antibody transfer. Two weeks after the last vaccination, whole IgG was purified from serum, and 2 mg was transferred to naive CD1 mice (PvTRAP IgG). Whole IgG raised against empty viral vectors was also included (control IgG).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3957994&req=5

Figure 5: Protection against sporozoite challenge is mediated by both PvTRAP-specific CD8+ T cells and antibodies. (a) Flow cytometry analysis of PBMCs from mice, indicating that injection of anti-GK1.5 or anti-2.43 was approximately 99% effective at depleting CD4+ or CD8+ cells, respectively. rlgG1 MAb served as a negative control. (b and c) Effect of depletion of CD4+ or CD8+ T cells on protection against parasite challenge. BALB/c and CD1 mice (n = 12) were first vaccinated using a heterologous prime-boost regimen with Ad-MVA expressing PvTRAP. Two weeks after the final vaccination, the mice received depleting anti-GK1.5 or anti-2.43 antibodies on days −2, −1, and 0 relative to the challenge. P values were generated using a Kaplan-Meyer method to compare survival curves. n.s., not significant. (d) Survival curve of CD1 mice upon PvTRAP antibody transfer. Two weeks after the last vaccination, whole IgG was purified from serum, and 2 mg was transferred to naive CD1 mice (PvTRAP IgG). Whole IgG raised against empty viral vectors was also included (control IgG).
Mentions: We further investigated the immune mechanisms associated with protection in a PvTRAP transgenic sporozoite challenge. CD4+ or CD8+ T cells were depleted by administration of the monoclonal antibody GK1.5, which binds to the CD4+ molecule, or the monoclonal antibody 2.43, which binds to the CD8+ molecule, both of which induce the depletion in blood of cells bearing these coreceptors (Fig. 5a). Antibodies were administered on three consecutive days after a boosting vaccine with MVA-PvTRAP, which corresponded to days −2, −1, and 0 with respect to the time of the sporozoite challenge.

Bottom Line: Plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America.Using this model, we found that both CD8+ T cells and antibodies mediated protection against malaria using virus-vectored vaccines.Our data indicate that ChAd63 and MVA expressing PvTRAP are good preerythrocytic-stage vaccine candidates with potential for future clinical application.

View Article: PubMed Central - PubMed

Affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America. Despite this dramatic burden, very few vaccines have been assessed in humans. The clinically relevant vectors modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAd63 are promising delivery systems for malaria vaccines due to their safety profiles and proven ability to induce protective immune responses against Plasmodium falciparum thrombospondin-related anonymous protein (TRAP) in clinical trials. Here, we describe the development of new recombinant ChAd63 and MVA vectors expressing P. vivax TRAP (PvTRAP) and show their ability to induce high antibody titers and T cell responses in mice. In addition, we report a novel way of assessing the efficacy of new candidate vaccines against P. vivax using a fully infectious transgenic Plasmodium berghei parasite expressing P. vivax TRAP to allow studies of vaccine efficacy and protective mechanisms in rodents. Using this model, we found that both CD8+ T cells and antibodies mediated protection against malaria using virus-vectored vaccines. Our data indicate that ChAd63 and MVA expressing PvTRAP are good preerythrocytic-stage vaccine candidates with potential for future clinical application.

Show MeSH
Related in: MedlinePlus