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Age at Mycobacterium bovis BCG Priming Has Limited Impact on Anti-Tuberculosis Immunity Boosted by Respiratory Mucosal AdHu5Ag85A Immunization in a Murine Model.

Damjanovic D, Khera A, Afkhami S, Lai R, Zganiacz A, Jeyanathan M, Xing Z - PLoS ONE (2015)

Bottom Line: Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB.Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection.However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization.

View Article: PubMed Central - PubMed

Affiliation: McMaster Immunology Research Centre and Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

ABSTRACT
Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB. The introduction of novel boost vaccines such as the human Adenovirus 5-vectored AdHu5Ag85A could improve and prolong the protective immunity of BCG immunization. Age at which BCG immunization is implemented varies greatly worldwide, and research is ongoing to discover the optimal stage during childhood to administer the vaccine, as well as when to boost the immune response with potential novel vaccines. Using a murine model of subcutaneous BCG immunization followed by intranasal AdHu5Ag85A boosting, we investigated the impact of age at BCG immunization on protective efficacy of BCG prime and AdHu5Ag85A boost immunization-mediated protection. Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection. However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization. Our findings hold implications for the design of new TB immunization protocols for humans.

No MeSH data available.


Related in: MedlinePlus

Effect of elapsed time between BCG priming and AdHu5Ag85A boost immunization on Ag-specific responses boosted by AdHu5Ag85A boost immunization.Infant and adult mice were BCG immunized, and boosted with AdHu5Ag85A at 8 or 16 weeks post-BCG (A). The mice were sacrificed 4 weeks after boosting. Cells isolated from the lung were stimulated either with M.tb CF + crude BCG (B), Ag85A-specific CD4 T cell peptide (C), or CD8 T cell peptide (D), or left unstimulated as a control. Cells were stained and analyzed by flow cytometry. Absolute numbers of IFN-γ+CD4+ (B, C) and IFN-γ+CD8+ (D) T cells were calculated (unstimulated subtracted from stimulated). Ag85A CD8 peptide tetramer staining was performed on lung cells, and analyzed by flow cytometry (E). Absolute numbers of tet+CD8+ T cells were calculated. Results are from one experiment per timepoint, n = 4-5/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05; **, p < 0.005; ***, p < 0.0005. All other comparisons (not indicated) were not significant.
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pone.0131175.g006: Effect of elapsed time between BCG priming and AdHu5Ag85A boost immunization on Ag-specific responses boosted by AdHu5Ag85A boost immunization.Infant and adult mice were BCG immunized, and boosted with AdHu5Ag85A at 8 or 16 weeks post-BCG (A). The mice were sacrificed 4 weeks after boosting. Cells isolated from the lung were stimulated either with M.tb CF + crude BCG (B), Ag85A-specific CD4 T cell peptide (C), or CD8 T cell peptide (D), or left unstimulated as a control. Cells were stained and analyzed by flow cytometry. Absolute numbers of IFN-γ+CD4+ (B, C) and IFN-γ+CD8+ (D) T cells were calculated (unstimulated subtracted from stimulated). Ag85A CD8 peptide tetramer staining was performed on lung cells, and analyzed by flow cytometry (E). Absolute numbers of tet+CD8+ T cells were calculated. Results are from one experiment per timepoint, n = 4-5/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05; **, p < 0.005; ***, p < 0.0005. All other comparisons (not indicated) were not significant.

Mentions: An optimal interval between priming and boosting is critical to elicit ideal levels of antigen-specific immune responses. Thus we next analyzed the relation between time elapsed from the BCG priming and AdHu5Ag85A boosting on the activation of Ag-specific T cells. A group of infant and a group of adult mice were immunized with BCG (Fig 6A). At 8 or 16 weeks post-BCG immunization a set of mice immunized as infants or adults were immunized with AdHu5Ag85A (BCG/AdHu5Ag85A) and 4 weeks later antigen-specific responses in the lung were enumerated using flow cytometry (Fig 6A). Lung mononuclear cells were stimulated with either CF+cBCG or Ag85A CD4 or CD8 peptides and analyzed for Ag-specific IFN-γ+CD4+ and IFN-γ+CD8+ responses. In addition, lung mononuclear cells were stained for Ag85A CD8 tetramer. In contrast to mice immunized as adults, levels of crude mycobacterial antigen (CF+cBCG) reactive CD4 T cells (Fig 6B) and Ag85A-specific CD4 T cells (Fig 6C) in the lung of mice immunized as infants significantly decreased as elapsed time between BCG priming and AdHu5Ag85A boost immunization was extended from 8 to 16 weeks. On the other hand Ag85A-specific CD8 responses in mice immunized as infants were not affected by increasing the elapsed time between BCG priming and AdHu5Ag85A boosting (Fig 6D). However, extended elapsed time for AdHu5Ag85A boost in mice BCG immunized as adults led to enhanced tet+CD8+ responses (Fig 6E). Furthermore, delaying the BCG prime immunization from infancy to adulthood resulted in enhanced T cell responses in the lung after AdHu5Ag85A boosting at 16 weeks post-BCG. Together these results indicate that elapsed time between parenteral BCG prime immunization and respiratory mucosal AdHu5Ag85A boost immunization in mice BCG immunized as infants or adults differently affects boost effect of AdHu5Ag85A.


Age at Mycobacterium bovis BCG Priming Has Limited Impact on Anti-Tuberculosis Immunity Boosted by Respiratory Mucosal AdHu5Ag85A Immunization in a Murine Model.

Damjanovic D, Khera A, Afkhami S, Lai R, Zganiacz A, Jeyanathan M, Xing Z - PLoS ONE (2015)

Effect of elapsed time between BCG priming and AdHu5Ag85A boost immunization on Ag-specific responses boosted by AdHu5Ag85A boost immunization.Infant and adult mice were BCG immunized, and boosted with AdHu5Ag85A at 8 or 16 weeks post-BCG (A). The mice were sacrificed 4 weeks after boosting. Cells isolated from the lung were stimulated either with M.tb CF + crude BCG (B), Ag85A-specific CD4 T cell peptide (C), or CD8 T cell peptide (D), or left unstimulated as a control. Cells were stained and analyzed by flow cytometry. Absolute numbers of IFN-γ+CD4+ (B, C) and IFN-γ+CD8+ (D) T cells were calculated (unstimulated subtracted from stimulated). Ag85A CD8 peptide tetramer staining was performed on lung cells, and analyzed by flow cytometry (E). Absolute numbers of tet+CD8+ T cells were calculated. Results are from one experiment per timepoint, n = 4-5/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05; **, p < 0.005; ***, p < 0.0005. All other comparisons (not indicated) were not significant.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4476612&req=5

pone.0131175.g006: Effect of elapsed time between BCG priming and AdHu5Ag85A boost immunization on Ag-specific responses boosted by AdHu5Ag85A boost immunization.Infant and adult mice were BCG immunized, and boosted with AdHu5Ag85A at 8 or 16 weeks post-BCG (A). The mice were sacrificed 4 weeks after boosting. Cells isolated from the lung were stimulated either with M.tb CF + crude BCG (B), Ag85A-specific CD4 T cell peptide (C), or CD8 T cell peptide (D), or left unstimulated as a control. Cells were stained and analyzed by flow cytometry. Absolute numbers of IFN-γ+CD4+ (B, C) and IFN-γ+CD8+ (D) T cells were calculated (unstimulated subtracted from stimulated). Ag85A CD8 peptide tetramer staining was performed on lung cells, and analyzed by flow cytometry (E). Absolute numbers of tet+CD8+ T cells were calculated. Results are from one experiment per timepoint, n = 4-5/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05; **, p < 0.005; ***, p < 0.0005. All other comparisons (not indicated) were not significant.
Mentions: An optimal interval between priming and boosting is critical to elicit ideal levels of antigen-specific immune responses. Thus we next analyzed the relation between time elapsed from the BCG priming and AdHu5Ag85A boosting on the activation of Ag-specific T cells. A group of infant and a group of adult mice were immunized with BCG (Fig 6A). At 8 or 16 weeks post-BCG immunization a set of mice immunized as infants or adults were immunized with AdHu5Ag85A (BCG/AdHu5Ag85A) and 4 weeks later antigen-specific responses in the lung were enumerated using flow cytometry (Fig 6A). Lung mononuclear cells were stimulated with either CF+cBCG or Ag85A CD4 or CD8 peptides and analyzed for Ag-specific IFN-γ+CD4+ and IFN-γ+CD8+ responses. In addition, lung mononuclear cells were stained for Ag85A CD8 tetramer. In contrast to mice immunized as adults, levels of crude mycobacterial antigen (CF+cBCG) reactive CD4 T cells (Fig 6B) and Ag85A-specific CD4 T cells (Fig 6C) in the lung of mice immunized as infants significantly decreased as elapsed time between BCG priming and AdHu5Ag85A boost immunization was extended from 8 to 16 weeks. On the other hand Ag85A-specific CD8 responses in mice immunized as infants were not affected by increasing the elapsed time between BCG priming and AdHu5Ag85A boosting (Fig 6D). However, extended elapsed time for AdHu5Ag85A boost in mice BCG immunized as adults led to enhanced tet+CD8+ responses (Fig 6E). Furthermore, delaying the BCG prime immunization from infancy to adulthood resulted in enhanced T cell responses in the lung after AdHu5Ag85A boosting at 16 weeks post-BCG. Together these results indicate that elapsed time between parenteral BCG prime immunization and respiratory mucosal AdHu5Ag85A boost immunization in mice BCG immunized as infants or adults differently affects boost effect of AdHu5Ag85A.

Bottom Line: Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB.Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection.However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization.

View Article: PubMed Central - PubMed

Affiliation: McMaster Immunology Research Centre and Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

ABSTRACT
Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB. The introduction of novel boost vaccines such as the human Adenovirus 5-vectored AdHu5Ag85A could improve and prolong the protective immunity of BCG immunization. Age at which BCG immunization is implemented varies greatly worldwide, and research is ongoing to discover the optimal stage during childhood to administer the vaccine, as well as when to boost the immune response with potential novel vaccines. Using a murine model of subcutaneous BCG immunization followed by intranasal AdHu5Ag85A boosting, we investigated the impact of age at BCG immunization on protective efficacy of BCG prime and AdHu5Ag85A boost immunization-mediated protection. Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection. However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization. Our findings hold implications for the design of new TB immunization protocols for humans.

No MeSH data available.


Related in: MedlinePlus