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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.

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Measures of tuberculosis-induced pulmonary and clinical disease burden. Panel A: the lung to lesion volume ratio determined using MR stereology; Panel B: number of lesions in the lung enumerated by serial sectioning and manual counting; Panel C: the score attributed to the pulmonary component as part of the total pathology; Panel D: the total pathology score determined using a qualitative scoring system; Panel E: score attributed to the chest radiogram on the day of euthanasia; Panel F: % weight loss from peak post-challenge weight on the day of euthanasia; Panel G: Erythrocyte sedimentation rate (ESR) on the day of euthanasia; Panel H: bacterial load in the lung. Red shading indicates animals in which disease reached endpoint criteria. P values are shown and * denotes significant difference in outcome between groups using the non-parametric Mann-Whitney U test, p ≤ 0.05.
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fig2: Measures of tuberculosis-induced pulmonary and clinical disease burden. Panel A: the lung to lesion volume ratio determined using MR stereology; Panel B: number of lesions in the lung enumerated by serial sectioning and manual counting; Panel C: the score attributed to the pulmonary component as part of the total pathology; Panel D: the total pathology score determined using a qualitative scoring system; Panel E: score attributed to the chest radiogram on the day of euthanasia; Panel F: % weight loss from peak post-challenge weight on the day of euthanasia; Panel G: Erythrocyte sedimentation rate (ESR) on the day of euthanasia; Panel H: bacterial load in the lung. Red shading indicates animals in which disease reached endpoint criteria. P values are shown and * denotes significant difference in outcome between groups using the non-parametric Mann-Whitney U test, p ≤ 0.05.

Mentions: The macaques were challenged with a median estimated retained dose of 94 cfu (range 74–174) (Table 1) and the doses were consistent across all the study groups. In the period after aerosol challenge with M. tb, a proportion of animals in all four study groups showed changes in behaviour and clinical parameters consistent with progression of tuberculosis-induced disease and were euthanized ahead of the planned end of the study. These animals included five of the six naïve control group D (S23, S33, S36, S40, S51), three of six ID BCG-vaccinated animals in group A (S43, S6, S17), two of six ID + IT BCG vaccinated animals in group B (S42, S12) and one of six IV BCG vaccinated animals in group C (S35), and all exhibited progressive weight loss, elevated ESR levels, erythrocyte haemoglobin concentrations below the normal range, tachypnoea and or dyspnoea and cough (red symbols, Fig. 2E–H). None of the surviving animals in any vaccination group showed adverse behavioural or pre-mortem clinical indicators at the time of termination 17–20 weeks after challenge (Fig. 2E–H).


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
Measures of tuberculosis-induced pulmonary and clinical disease burden. Panel A: the lung to lesion volume ratio determined using MR stereology; Panel B: number of lesions in the lung enumerated by serial sectioning and manual counting; Panel C: the score attributed to the pulmonary component as part of the total pathology; Panel D: the total pathology score determined using a qualitative scoring system; Panel E: score attributed to the chest radiogram on the day of euthanasia; Panel F: % weight loss from peak post-challenge weight on the day of euthanasia; Panel G: Erythrocyte sedimentation rate (ESR) on the day of euthanasia; Panel H: bacterial load in the lung. Red shading indicates animals in which disease reached endpoint criteria. P values are shown and * denotes significant difference in outcome between groups using the non-parametric Mann-Whitney U test, p ≤ 0.05.
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Related In: Results  -  Collection

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Show All Figures
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fig2: Measures of tuberculosis-induced pulmonary and clinical disease burden. Panel A: the lung to lesion volume ratio determined using MR stereology; Panel B: number of lesions in the lung enumerated by serial sectioning and manual counting; Panel C: the score attributed to the pulmonary component as part of the total pathology; Panel D: the total pathology score determined using a qualitative scoring system; Panel E: score attributed to the chest radiogram on the day of euthanasia; Panel F: % weight loss from peak post-challenge weight on the day of euthanasia; Panel G: Erythrocyte sedimentation rate (ESR) on the day of euthanasia; Panel H: bacterial load in the lung. Red shading indicates animals in which disease reached endpoint criteria. P values are shown and * denotes significant difference in outcome between groups using the non-parametric Mann-Whitney U test, p ≤ 0.05.
Mentions: The macaques were challenged with a median estimated retained dose of 94 cfu (range 74–174) (Table 1) and the doses were consistent across all the study groups. In the period after aerosol challenge with M. tb, a proportion of animals in all four study groups showed changes in behaviour and clinical parameters consistent with progression of tuberculosis-induced disease and were euthanized ahead of the planned end of the study. These animals included five of the six naïve control group D (S23, S33, S36, S40, S51), three of six ID BCG-vaccinated animals in group A (S43, S6, S17), two of six ID + IT BCG vaccinated animals in group B (S42, S12) and one of six IV BCG vaccinated animals in group C (S35), and all exhibited progressive weight loss, elevated ESR levels, erythrocyte haemoglobin concentrations below the normal range, tachypnoea and or dyspnoea and cough (red symbols, Fig. 2E–H). None of the surviving animals in any vaccination group showed adverse behavioural or pre-mortem clinical indicators at the time of termination 17–20 weeks after challenge (Fig. 2E–H).

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