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Preclinical development of an in vivo BCG challenge model for testing candidate TB vaccine efficacy.

Minassian AM, Ronan EO, Poyntz H, Hill AV, McShane H - PLoS ONE (2011)

Bottom Line: Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin.Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge.Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection.

View Article: PubMed Central - PubMed

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

ABSTRACT
There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection.

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Effect of BCG on a 4-week id and in BCG challenge.BALB/c mice were immunized id with 2.5×103 CFU BCG. Naïve and antibiotic-treated (I+R) mice received no immunization. Four weeks later all mice were challenged either id or in with 4×103 CFU BCG, except the BCG control group who received no challenge. Immediately post-challenge the I+R group was treated for 4 weeks with isoniazid and rifampicin. Ears (a), LNs (b) and lungs (c) were harvested 4 weeks after challenge (spleen cfu data not shown). (d) shows the effect of in BCG on in challenge in a separate experiment. Here, BALB/c mice were immunized in with 1×103 CFU BCG. Naïve mice received no immunization. 4 weeks later in-immunized and naïve mice were challenged with 4×104 CFU BCG in. The “BCG in control” group received no challenge. Lungs were harvested 4 weeks after BCG challenge in all groups. CFU from plating of fresh tissues are shown. Log10 BCG CFU individual data points for each mouse are shown. Bars represent the median per group. (a) Ears (**P<0.01, n = 10); (b) LNs (**P<0.01, n = 10); (c) Lungs (**P<0.01, n = 10); (d) Lungs P<0.01, n = 8 naïve; n = 6 BCG in; n = 8 BCG in control).
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pone-0019840-g004: Effect of BCG on a 4-week id and in BCG challenge.BALB/c mice were immunized id with 2.5×103 CFU BCG. Naïve and antibiotic-treated (I+R) mice received no immunization. Four weeks later all mice were challenged either id or in with 4×103 CFU BCG, except the BCG control group who received no challenge. Immediately post-challenge the I+R group was treated for 4 weeks with isoniazid and rifampicin. Ears (a), LNs (b) and lungs (c) were harvested 4 weeks after challenge (spleen cfu data not shown). (d) shows the effect of in BCG on in challenge in a separate experiment. Here, BALB/c mice were immunized in with 1×103 CFU BCG. Naïve mice received no immunization. 4 weeks later in-immunized and naïve mice were challenged with 4×104 CFU BCG in. The “BCG in control” group received no challenge. Lungs were harvested 4 weeks after BCG challenge in all groups. CFU from plating of fresh tissues are shown. Log10 BCG CFU individual data points for each mouse are shown. Bars represent the median per group. (a) Ears (**P<0.01, n = 10); (b) LNs (**P<0.01, n = 10); (c) Lungs (**P<0.01, n = 10); (d) Lungs P<0.01, n = 8 naïve; n = 6 BCG in; n = 8 BCG in control).

Mentions: We next investigated whether the protective effect of BCG immunization was dose dependent. A comparable reduction in the CFU count of challenge was seen when a 1-log reduced BCG immunization dose of 2.5×103 CFU was administered (P = 0.0005, Fig. 4a). The challenge dose administered was the same as for the previous experiment. There was also a significant reduction in the LN CFU counts (P = 0.0005, Fig. 4b).


Preclinical development of an in vivo BCG challenge model for testing candidate TB vaccine efficacy.

Minassian AM, Ronan EO, Poyntz H, Hill AV, McShane H - PLoS ONE (2011)

Effect of BCG on a 4-week id and in BCG challenge.BALB/c mice were immunized id with 2.5×103 CFU BCG. Naïve and antibiotic-treated (I+R) mice received no immunization. Four weeks later all mice were challenged either id or in with 4×103 CFU BCG, except the BCG control group who received no challenge. Immediately post-challenge the I+R group was treated for 4 weeks with isoniazid and rifampicin. Ears (a), LNs (b) and lungs (c) were harvested 4 weeks after challenge (spleen cfu data not shown). (d) shows the effect of in BCG on in challenge in a separate experiment. Here, BALB/c mice were immunized in with 1×103 CFU BCG. Naïve mice received no immunization. 4 weeks later in-immunized and naïve mice were challenged with 4×104 CFU BCG in. The “BCG in control” group received no challenge. Lungs were harvested 4 weeks after BCG challenge in all groups. CFU from plating of fresh tissues are shown. Log10 BCG CFU individual data points for each mouse are shown. Bars represent the median per group. (a) Ears (**P<0.01, n = 10); (b) LNs (**P<0.01, n = 10); (c) Lungs (**P<0.01, n = 10); (d) Lungs P<0.01, n = 8 naïve; n = 6 BCG in; n = 8 BCG in control).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3101220&req=5

pone-0019840-g004: Effect of BCG on a 4-week id and in BCG challenge.BALB/c mice were immunized id with 2.5×103 CFU BCG. Naïve and antibiotic-treated (I+R) mice received no immunization. Four weeks later all mice were challenged either id or in with 4×103 CFU BCG, except the BCG control group who received no challenge. Immediately post-challenge the I+R group was treated for 4 weeks with isoniazid and rifampicin. Ears (a), LNs (b) and lungs (c) were harvested 4 weeks after challenge (spleen cfu data not shown). (d) shows the effect of in BCG on in challenge in a separate experiment. Here, BALB/c mice were immunized in with 1×103 CFU BCG. Naïve mice received no immunization. 4 weeks later in-immunized and naïve mice were challenged with 4×104 CFU BCG in. The “BCG in control” group received no challenge. Lungs were harvested 4 weeks after BCG challenge in all groups. CFU from plating of fresh tissues are shown. Log10 BCG CFU individual data points for each mouse are shown. Bars represent the median per group. (a) Ears (**P<0.01, n = 10); (b) LNs (**P<0.01, n = 10); (c) Lungs (**P<0.01, n = 10); (d) Lungs P<0.01, n = 8 naïve; n = 6 BCG in; n = 8 BCG in control).
Mentions: We next investigated whether the protective effect of BCG immunization was dose dependent. A comparable reduction in the CFU count of challenge was seen when a 1-log reduced BCG immunization dose of 2.5×103 CFU was administered (P = 0.0005, Fig. 4a). The challenge dose administered was the same as for the previous experiment. There was also a significant reduction in the LN CFU counts (P = 0.0005, Fig. 4b).

Bottom Line: Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin.Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge.Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection.

View Article: PubMed Central - PubMed

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

ABSTRACT
There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection.

Show MeSH
Related in: MedlinePlus