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A human challenge model for Mycobacterium tuberculosis using Mycobacterium bovis bacille Calmette-Guerin.

Minassian AM, Satti I, Poulton ID, Meyer J, Hill AV, McShane H - J. Infect. Dis. (2012)

Bottom Line: There was no significant correlation between BCG load after challenge and mycobacterial-specific memory T cells measured before challenge by cultured enzyme-linked immunospot assay.This novel experimental human challenge model provides a platform for the identification of correlates of antimycobacterial immunity and will greatly facilitate the rational down-selection of candidate tuberculosis vaccines.Further evaluation of this model with BCG and new vaccine candidates is warranted.

View Article: PubMed Central - PubMed

Affiliation: The Jenner Institute, University of Oxford, UK. minassian.angela@gmail.com

ABSTRACT

Background: There is currently no safe human challenge model of Mycobacterium tuberculosis infection to enable proof-of-concept efficacy evaluation of candidate vaccines against tuberculosis. In vivo antimycobacterial immunity could be assessed using intradermal Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination as a surrogate for M. tuberculosis infection.

Methods: Healthy BCG-naive and BCG-vaccinated volunteers were challenged with intradermal BCG. BCG load was quantified from skin biopsy specimens by polymerase chain reaction (PCR) and culture colony-forming units. Cellular infiltrate was isolated by suction blisters and examined by flow cytometry. Prechallenge immune readouts were correlated with BCG load after challenge.

Results: In BCG-naive volunteers, live BCG was detected at the challenge site for up to 4 weeks and peaked at 2 weeks. Infiltration of mainly CD15(+) neutrophils was observed in blister fluid. In previously BCG-vaccinated individuals, PCR analysis of skin biopsy specimens reflected a degree of mycobacterial immunity. There was no significant correlation between BCG load after challenge and mycobacterial-specific memory T cells measured before challenge by cultured enzyme-linked immunospot assay.

Conclusions: This novel experimental human challenge model provides a platform for the identification of correlates of antimycobacterial immunity and will greatly facilitate the rational down-selection of candidate tuberculosis vaccines. Further evaluation of this model with BCG and new vaccine candidates is warranted.

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Related in: MedlinePlus

Variability in postchallenge colony-forming unit (CFU) counts in bacille Calmette-Guérin (BCG)–vaccinated humans. A, Comparison between culture and polymerase chain reaction (PCR) challenge results in BCG-vaccinated volunteers, log scale. B, Correlation between culture (CFU count) and PCR (Spearman rank). Comparison of PCR and culture challenge results in naive (NAIVE–BCG) and BCG-vaccinated (BCG1–BCG2) volunteers. C, PCR values (BCG copies [log10] per biopsy specimen, corrected for nanograms of DNA extracted) in BCG-naive and BCG-vaccinated groups. D, Corresponding culture values (log10 BCG CFU count per biopsy specimen). Exact P values are shown.
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fig2: Variability in postchallenge colony-forming unit (CFU) counts in bacille Calmette-Guérin (BCG)–vaccinated humans. A, Comparison between culture and polymerase chain reaction (PCR) challenge results in BCG-vaccinated volunteers, log scale. B, Correlation between culture (CFU count) and PCR (Spearman rank). Comparison of PCR and culture challenge results in naive (NAIVE–BCG) and BCG-vaccinated (BCG1–BCG2) volunteers. C, PCR values (BCG copies [log10] per biopsy specimen, corrected for nanograms of DNA extracted) in BCG-naive and BCG-vaccinated groups. D, Corresponding culture values (log10 BCG CFU count per biopsy specimen). Exact P values are shown.

Mentions: The PCR and culture data for the group with prior BCG vaccination are shown in Figure 2A. Within this group, there was a strong correlation between the 2 methods of bacterial quantification 2 weeks after challenge (R = 0.87; P = .0002) (Figure 2B). This correlation was stronger than for the corresponding BCG-naive group (R = 0.77; P = .004).


A human challenge model for Mycobacterium tuberculosis using Mycobacterium bovis bacille Calmette-Guerin.

Minassian AM, Satti I, Poulton ID, Meyer J, Hill AV, McShane H - J. Infect. Dis. (2012)

Variability in postchallenge colony-forming unit (CFU) counts in bacille Calmette-Guérin (BCG)–vaccinated humans. A, Comparison between culture and polymerase chain reaction (PCR) challenge results in BCG-vaccinated volunteers, log scale. B, Correlation between culture (CFU count) and PCR (Spearman rank). Comparison of PCR and culture challenge results in naive (NAIVE–BCG) and BCG-vaccinated (BCG1–BCG2) volunteers. C, PCR values (BCG copies [log10] per biopsy specimen, corrected for nanograms of DNA extracted) in BCG-naive and BCG-vaccinated groups. D, Corresponding culture values (log10 BCG CFU count per biopsy specimen). Exact P values are shown.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3295601&req=5

fig2: Variability in postchallenge colony-forming unit (CFU) counts in bacille Calmette-Guérin (BCG)–vaccinated humans. A, Comparison between culture and polymerase chain reaction (PCR) challenge results in BCG-vaccinated volunteers, log scale. B, Correlation between culture (CFU count) and PCR (Spearman rank). Comparison of PCR and culture challenge results in naive (NAIVE–BCG) and BCG-vaccinated (BCG1–BCG2) volunteers. C, PCR values (BCG copies [log10] per biopsy specimen, corrected for nanograms of DNA extracted) in BCG-naive and BCG-vaccinated groups. D, Corresponding culture values (log10 BCG CFU count per biopsy specimen). Exact P values are shown.
Mentions: The PCR and culture data for the group with prior BCG vaccination are shown in Figure 2A. Within this group, there was a strong correlation between the 2 methods of bacterial quantification 2 weeks after challenge (R = 0.87; P = .0002) (Figure 2B). This correlation was stronger than for the corresponding BCG-naive group (R = 0.77; P = .004).

Bottom Line: There was no significant correlation between BCG load after challenge and mycobacterial-specific memory T cells measured before challenge by cultured enzyme-linked immunospot assay.This novel experimental human challenge model provides a platform for the identification of correlates of antimycobacterial immunity and will greatly facilitate the rational down-selection of candidate tuberculosis vaccines.Further evaluation of this model with BCG and new vaccine candidates is warranted.

View Article: PubMed Central - PubMed

Affiliation: The Jenner Institute, University of Oxford, UK. minassian.angela@gmail.com

ABSTRACT

Background: There is currently no safe human challenge model of Mycobacterium tuberculosis infection to enable proof-of-concept efficacy evaluation of candidate vaccines against tuberculosis. In vivo antimycobacterial immunity could be assessed using intradermal Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination as a surrogate for M. tuberculosis infection.

Methods: Healthy BCG-naive and BCG-vaccinated volunteers were challenged with intradermal BCG. BCG load was quantified from skin biopsy specimens by polymerase chain reaction (PCR) and culture colony-forming units. Cellular infiltrate was isolated by suction blisters and examined by flow cytometry. Prechallenge immune readouts were correlated with BCG load after challenge.

Results: In BCG-naive volunteers, live BCG was detected at the challenge site for up to 4 weeks and peaked at 2 weeks. Infiltration of mainly CD15(+) neutrophils was observed in blister fluid. In previously BCG-vaccinated individuals, PCR analysis of skin biopsy specimens reflected a degree of mycobacterial immunity. There was no significant correlation between BCG load after challenge and mycobacterial-specific memory T cells measured before challenge by cultured enzyme-linked immunospot assay.

Conclusions: This novel experimental human challenge model provides a platform for the identification of correlates of antimycobacterial immunity and will greatly facilitate the rational down-selection of candidate tuberculosis vaccines. Further evaluation of this model with BCG and new vaccine candidates is warranted.

Show MeSH
Related in: MedlinePlus