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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

Relationship between PPD-specific IFN-γ SFU measured by ELISpot and frequency of antigen-specific CD4 TransEM populations. Correlation plots comparing the PPD-specific SFU measured by ELISpot and frequency of antigen-specific CD4 Transitional effector T-cell populations at six (A), 12 (B), 23 (C) and 25 (D) weeks following primary BCG vaccination. Note that week 23 and 25 also correspond to weeks two and four following aerosol M. tuberculosis infection, respectively (C and D). Data points represent individual animals. Spearman's correlation coefficient (r) and significance values (p) are indicated. A linear regression line is included for reference.
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fig8: Relationship between PPD-specific IFN-γ SFU measured by ELISpot and frequency of antigen-specific CD4 TransEM populations. Correlation plots comparing the PPD-specific SFU measured by ELISpot and frequency of antigen-specific CD4 Transitional effector T-cell populations at six (A), 12 (B), 23 (C) and 25 (D) weeks following primary BCG vaccination. Note that week 23 and 25 also correspond to weeks two and four following aerosol M. tuberculosis infection, respectively (C and D). Data points represent individual animals. Spearman's correlation coefficient (r) and significance values (p) are indicated. A linear regression line is included for reference.

Mentions: The ex vivo IFN-γ ELISpot assay applied throughout this study is commonly assumed to provide a rapid readout of Th1 effector T-cell function. To investigate the relationship between PPD-specific immune responses measured by IFN-γ ELISpot and antigen-specific memory T-cell phenotype, Spearman's correlation analysis was used to compare IFN-γ SFU and antigen-specific CD4 memory T-cell frequencies measured at equivalent time-points (Fig. 8). This revealed significant correlations between IFN-γ SFU measured by ELISpot assay and antigen-specific CD4 transitional effector memory T-cell frequency at study weeks six, 12, 23 and 25 post-vaccination (p = 0.0001 to 0.02, r = 0.515 to 0.867, respectively). This indicated that ex vivo IFN-γ SFU measured by ELISpot assay provides a useful measure of CD4 TransEM activity.


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
Relationship between PPD-specific IFN-γ SFU measured by ELISpot and frequency of antigen-specific CD4 TransEM populations. Correlation plots comparing the PPD-specific SFU measured by ELISpot and frequency of antigen-specific CD4 Transitional effector T-cell populations at six (A), 12 (B), 23 (C) and 25 (D) weeks following primary BCG vaccination. Note that week 23 and 25 also correspond to weeks two and four following aerosol M. tuberculosis infection, respectively (C and D). Data points represent individual animals. Spearman's correlation coefficient (r) and significance values (p) are indicated. A linear regression line is included for reference.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

fig8: Relationship between PPD-specific IFN-γ SFU measured by ELISpot and frequency of antigen-specific CD4 TransEM populations. Correlation plots comparing the PPD-specific SFU measured by ELISpot and frequency of antigen-specific CD4 Transitional effector T-cell populations at six (A), 12 (B), 23 (C) and 25 (D) weeks following primary BCG vaccination. Note that week 23 and 25 also correspond to weeks two and four following aerosol M. tuberculosis infection, respectively (C and D). Data points represent individual animals. Spearman's correlation coefficient (r) and significance values (p) are indicated. A linear regression line is included for reference.
Mentions: The ex vivo IFN-γ ELISpot assay applied throughout this study is commonly assumed to provide a rapid readout of Th1 effector T-cell function. To investigate the relationship between PPD-specific immune responses measured by IFN-γ ELISpot and antigen-specific memory T-cell phenotype, Spearman's correlation analysis was used to compare IFN-γ SFU and antigen-specific CD4 memory T-cell frequencies measured at equivalent time-points (Fig. 8). This revealed significant correlations between IFN-γ SFU measured by ELISpot assay and antigen-specific CD4 transitional effector memory T-cell frequency at study weeks six, 12, 23 and 25 post-vaccination (p = 0.0001 to 0.02, r = 0.515 to 0.867, respectively). This indicated that ex vivo IFN-γ SFU measured by ELISpot assay provides a useful measure of CD4 TransEM activity.

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