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Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations

View Article: PubMed Central - PubMed

ABSTRACT

Intradermal (ID) BCG injection provides incomplete protection against TB in humans and experimental models. Alternative BCG vaccination strategies may improve protection in model species, including rhesus macaques. This study compares the immunogenicity and efficacy of BCG administered by ID and intravenous (IV) injection, or as an intratracheal mucosal boost (ID + IT), against aerosol challenge with Mycobacterium tuberculosis Erdman strain. Disease pathology was significantly reduced, and survival improved, by each BCG vaccination strategy, relative to unvaccinated animals. However, IV induced protection surpassed that achieved by all other routes, providing an opportunity to explore protective immunological mechanisms using antigen-specific IFN-γ ELISpot and polychromatic flow cytometry assays. IFN-γ spot forming units and multifunctional CD4 T-cell frequencies increased significantly following each vaccination regimen and were greatest following IV immunisation. Vaccine-induced multifunctional CD4 T-cells producing IFN-γ and TNF-α were associated with reduced disease pathology following subsequent M.tb challenge; however, high frequencies of this population following M.tb infection correlated with increased pathology. Cytokine producing T-cells primarily occupied the CD4 transitional effector memory phenotype, implicating this population as central to the mycobacterial response, potentially contributing to the stringent control observed in IV vaccinated animals. This study demonstrates the protective efficacy of IV BCG vaccination in rhesus macaques, offering a valuable tool for the interrogation of immunological mechanisms and potential correlates of protection.

No MeSH data available.


Related in: MedlinePlus

Antigen-specific CD4 and CD8 memory T-cell profiles measured in PBMCs. Plots A and C, show representative bivariate density plots showing central to effector memory T-cell populations, defined by patterns of CD28 and CCR7 staining on CD95 expressing CD4 (A) and CD8 (C) T-cells, overlaid with cytokine producing cells represented as dots. Plot B displays the frequency of antigen-specific cytokine producing memory CD4 T-cell populations during the vaccination and M.tb infection phase of the study. Box plots show interquartile range with medians indicated. Plot C displays the frequency of antigen-specific cytokine producing memory CD8 T-cell populations during the vaccination and M.tb infection phase of the study. Box plots show interquartile range with medians indicated.
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fig7: Antigen-specific CD4 and CD8 memory T-cell profiles measured in PBMCs. Plots A and C, show representative bivariate density plots showing central to effector memory T-cell populations, defined by patterns of CD28 and CCR7 staining on CD95 expressing CD4 (A) and CD8 (C) T-cells, overlaid with cytokine producing cells represented as dots. Plot B displays the frequency of antigen-specific cytokine producing memory CD4 T-cell populations during the vaccination and M.tb infection phase of the study. Box plots show interquartile range with medians indicated. Plot C displays the frequency of antigen-specific cytokine producing memory CD8 T-cell populations during the vaccination and M.tb infection phase of the study. Box plots show interquartile range with medians indicated.

Mentions: To establish the memory differentiation status of antigen-specific CD4 and CD8 T-cells, cytokine producing central and effector memory populations were identified in each subset as cells producing any of the cytokines IFN-γ, IL-2 or TNF-α and the activation marker CD95, followed by expression patterns of the co-stimulatory receptor CD28 and lymph node homing marker CCR7. Therefore, central to effector T-cell differentiation was determined on antigen-specific CD4 and CD8 T-cells as (TCM) CD28+CCR7+; CD28+CCR7- transitional effector memory (TransEM); and fully differentiated (TEM) CD28−CCR7− (Fig. 7b and d).


Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations
Antigen-specific CD4 and CD8 memory T-cell profiles measured in PBMCs. Plots A and C, show representative bivariate density plots showing central to effector memory T-cell populations, defined by patterns of CD28 and CCR7 staining on CD95 expressing CD4 (A) and CD8 (C) T-cells, overlaid with cytokine producing cells represented as dots. Plot B displays the frequency of antigen-specific cytokine producing memory CD4 T-cell populations during the vaccination and M.tb infection phase of the study. Box plots show interquartile range with medians indicated. Plot C displays the frequency of antigen-specific cytokine producing memory CD8 T-cell populations during the vaccination and M.tb infection phase of the study. Box plots show interquartile range with medians indicated.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120991&req=5

fig7: Antigen-specific CD4 and CD8 memory T-cell profiles measured in PBMCs. Plots A and C, show representative bivariate density plots showing central to effector memory T-cell populations, defined by patterns of CD28 and CCR7 staining on CD95 expressing CD4 (A) and CD8 (C) T-cells, overlaid with cytokine producing cells represented as dots. Plot B displays the frequency of antigen-specific cytokine producing memory CD4 T-cell populations during the vaccination and M.tb infection phase of the study. Box plots show interquartile range with medians indicated. Plot C displays the frequency of antigen-specific cytokine producing memory CD8 T-cell populations during the vaccination and M.tb infection phase of the study. Box plots show interquartile range with medians indicated.
Mentions: To establish the memory differentiation status of antigen-specific CD4 and CD8 T-cells, cytokine producing central and effector memory populations were identified in each subset as cells producing any of the cytokines IFN-γ, IL-2 or TNF-α and the activation marker CD95, followed by expression patterns of the co-stimulatory receptor CD28 and lymph node homing marker CCR7. Therefore, central to effector T-cell differentiation was determined on antigen-specific CD4 and CD8 T-cells as (TCM) CD28+CCR7+; CD28+CCR7- transitional effector memory (TransEM); and fully differentiated (TEM) CD28−CCR7− (Fig. 7b and d).

View Article: PubMed Central - PubMed

ABSTRACT

Intradermal (ID) BCG injection provides incomplete protection against TB in humans and experimental models. Alternative BCG vaccination strategies may improve protection in model species, including rhesus macaques. This study compares the immunogenicity and efficacy of BCG administered by ID and intravenous (IV) injection, or as an intratracheal mucosal boost (ID + IT), against aerosol challenge with Mycobacterium tuberculosis Erdman strain. Disease pathology was significantly reduced, and survival improved, by each BCG vaccination strategy, relative to unvaccinated animals. However, IV induced protection surpassed that achieved by all other routes, providing an opportunity to explore protective immunological mechanisms using antigen-specific IFN-γ ELISpot and polychromatic flow cytometry assays. IFN-γ spot forming units and multifunctional CD4 T-cell frequencies increased significantly following each vaccination regimen and were greatest following IV immunisation. Vaccine-induced multifunctional CD4 T-cells producing IFN-γ and TNF-α were associated with reduced disease pathology following subsequent M.tb challenge; however, high frequencies of this population following M.tb infection correlated with increased pathology. Cytokine producing T-cells primarily occupied the CD4 transitional effector memory phenotype, implicating this population as central to the mycobacterial response, potentially contributing to the stringent control observed in IV vaccinated animals. This study demonstrates the protective efficacy of IV BCG vaccination in rhesus macaques, offering a valuable tool for the interrogation of immunological mechanisms and potential correlates of protection.

No MeSH data available.


Related in: MedlinePlus