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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

Memory T cells in the lung and spleen of infant and adult mice following BCG immunization.Infant and adult mice were BCG immunized and sacrificed at 8 or 16 weeks. Cells from the lung (A) and spleen (B) were stained with extracellular antibodies for memory CD4 T cell markers and analyzed by flow cytometry. Absolute numbers of CD4+CD44+ cells that are Teff/TEM (CD127-/+CD62L-) or TCM (CD127+CD62L+) in the tissues were calculated. Results are from one experiment per timepoint, n = 4/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05.
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pone.0131175.g003: Memory T cells in the lung and spleen of infant and adult mice following BCG immunization.Infant and adult mice were BCG immunized and sacrificed at 8 or 16 weeks. Cells from the lung (A) and spleen (B) were stained with extracellular antibodies for memory CD4 T cell markers and analyzed by flow cytometry. Absolute numbers of CD4+CD44+ cells that are Teff/TEM (CD127-/+CD62L-) or TCM (CD127+CD62L+) in the tissues were calculated. Results are from one experiment per timepoint, n = 4/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05.

Mentions: Having established that age at BCG immunization does not affect the magnitude and functionality of antigen-specific T cells and that IL-2-producing antigen-specific CD4 T cells are generated in both groups, we next evaluated the memory phenotype of these cells. Of note, BCG vaccine-activated IL-2 expression has been previously shown to be associated with long-lived memory T cells with a central memory phenotype [32]. To differentiate between cells having the phenotype of Teff (effector), TEM (effector memory) and TCM (central memory), we evaluated the expression of multiple surface markers including CD44 (to identify activated T cells), CD62L, and CD127 [29]. In the lungs, levels of Teff /TEM (CD44+CD62L-CD127+/-) were similar between mice BCG immunized as infants and mice BCG immunized as adults at 8 and 16 weeks post-immunization (Fig 3A). Similarly, levels of central memory T cells (TCM) (CD44+CD62L+CD127+) were comparable between the two groups at 8 weeks (Fig 3A). In contrast, at 16 weeks post-immunization mice BCG immunized as adults had significantly higher levels of central memory T cells compared to mice immunized as infants (Fig 3A). Furthermore, while TCM cells significantly decreased in number overtime in mice BCG immunized as infants, they remained sustained in mice immunized as adults (Fig 3A). In contrast to the lung, levels of Teff /TEM cells were significantly higher in the spleen of mice BCG immunized as adults compared to mice immunized as infants at 8 weeks post-immunization (Fig 3B). However, such differences faded by 16 weeks (Fig 3B). In the spleen, a significantly increased number of TCM cells was observed in mice BCG immunized as adults compared to mice immunized as infants throughout the study period (Fig 3B). However, in both groups TCM cell numbers significantly decreased over time (Fig 3B). Taken together the above data suggest that BCG immunization in adult mice leads to generation of higher and sustained levels of central memory cells in the spleen compared to BCG immunization in infant mice.


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)

Memory T cells in the lung and spleen of infant and adult mice following BCG immunization.Infant and adult mice were BCG immunized and sacrificed at 8 or 16 weeks. Cells from the lung (A) and spleen (B) were stained with extracellular antibodies for memory CD4 T cell markers and analyzed by flow cytometry. Absolute numbers of CD4+CD44+ cells that are Teff/TEM (CD127-/+CD62L-) or TCM (CD127+CD62L+) in the tissues were calculated. Results are from one experiment per timepoint, n = 4/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131175.g003: Memory T cells in the lung and spleen of infant and adult mice following BCG immunization.Infant and adult mice were BCG immunized and sacrificed at 8 or 16 weeks. Cells from the lung (A) and spleen (B) were stained with extracellular antibodies for memory CD4 T cell markers and analyzed by flow cytometry. Absolute numbers of CD4+CD44+ cells that are Teff/TEM (CD127-/+CD62L-) or TCM (CD127+CD62L+) in the tissues were calculated. Results are from one experiment per timepoint, n = 4/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05.
Mentions: Having established that age at BCG immunization does not affect the magnitude and functionality of antigen-specific T cells and that IL-2-producing antigen-specific CD4 T cells are generated in both groups, we next evaluated the memory phenotype of these cells. Of note, BCG vaccine-activated IL-2 expression has been previously shown to be associated with long-lived memory T cells with a central memory phenotype [32]. To differentiate between cells having the phenotype of Teff (effector), TEM (effector memory) and TCM (central memory), we evaluated the expression of multiple surface markers including CD44 (to identify activated T cells), CD62L, and CD127 [29]. In the lungs, levels of Teff /TEM (CD44+CD62L-CD127+/-) were similar between mice BCG immunized as infants and mice BCG immunized as adults at 8 and 16 weeks post-immunization (Fig 3A). Similarly, levels of central memory T cells (TCM) (CD44+CD62L+CD127+) were comparable between the two groups at 8 weeks (Fig 3A). In contrast, at 16 weeks post-immunization mice BCG immunized as adults had significantly higher levels of central memory T cells compared to mice immunized as infants (Fig 3A). Furthermore, while TCM cells significantly decreased in number overtime in mice BCG immunized as infants, they remained sustained in mice immunized as adults (Fig 3A). In contrast to the lung, levels of Teff /TEM cells were significantly higher in the spleen of mice BCG immunized as adults compared to mice immunized as infants at 8 weeks post-immunization (Fig 3B). However, such differences faded by 16 weeks (Fig 3B). In the spleen, a significantly increased number of TCM cells was observed in mice BCG immunized as adults compared to mice immunized as infants throughout the study period (Fig 3B). However, in both groups TCM cell numbers significantly decreased over time (Fig 3B). Taken together the above data suggest that BCG immunization in adult mice leads to generation of higher and sustained levels of central memory cells in the spleen compared to BCG immunization in infant mice.

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