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Immunogenicity without Efficacy of an Adenoviral Tuberculosis Vaccine in a Stringent Mouse Model for Immunotherapy during Treatment.

Alyahya SA, Nolan ST, Smith CM, Bishai WR, Sadoff J, Lamichhane G - PLoS ONE (2015)

Bottom Line: Even though immunotherapy resulted in strong splenic IFN-γ responses, no effect on bacterial replication in the lungs was seen.Multiplex assay analysis of lung samples revealed the absence of cytokine augmentation such as IFN-γ, TNF-α and IL-2, suggesting that immunization failed to induce immunity in the lungs.The results obtained from our study raise questions regarding the traits of protective TB immunity that are relevant for the development of future immunotherapeutic and post-exposure vaccination strategies.

View Article: PubMed Central - PubMed

Affiliation: Crucell Holland B.V., Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands.

ABSTRACT
To investigate if bacterial persistence during TB drug treatment could be overcome by modulation of host immunity, we adapted a clinically-relevant model developed for the evaluation of new drugs and examined if immunotherapy with two adenoviral vaccines, Ad35-TBS (AERAS-402) and Ad26-TBS, could shorten therapy in mice. Even though immunotherapy resulted in strong splenic IFN-γ responses, no effect on bacterial replication in the lungs was seen. Multiplex assay analysis of lung samples revealed the absence of cytokine augmentation such as IFN-γ, TNF-α and IL-2, suggesting that immunization failed to induce immunity in the lungs. In this model, we show that IFN-γ levels were not associated with protection against disease relapse. The results obtained from our study raise questions regarding the traits of protective TB immunity that are relevant for the development of future immunotherapeutic and post-exposure vaccination strategies.

No MeSH data available.


Related in: MedlinePlus

Lung bacterial burden as measured by colony forming units (CFU) over time.At week -2, mice were infected via aerosol with M.tb at exponential phase of growth. One day following infection, 5 mice from the NC-IU group were sacrificed to determine the infection load. Following CFU enumeration at week 0, mice were randomized and treatment with R, H and Z was initiated for all groups except the NC-IU group as depicted in Fig 1. Mice from the chronically infected group, NC-IU, became progressively moribund and were sacrificed at week 12. At times indicated, immunotherapy with Ad35-TBS and Ad26-TBS were administered via intramuscular injections to the TV Ad35+ and TV Ad26+ animals, respectively. Animals in the NC-V and TV Ad26- received empty Ad35 and Ad26 vectors at the same immunotherapy time points. At week 16, treatment was truncated for mice in the NC-T4, TV Ad35+, NC-V, TV Ad26+ and TV Ad26-. Animals in the PC group received the full treatment through to week 24. CFU enumeration was conducted every 4 weeks following treatment cessation to monitor relapse in all groups that underwent therapy. The lower limit of detection was set at 10 CFU per total lung. Graph depicts the mean CFU value with standard deviation (n = 23, weeks 28 and 36). At all time points measured, no significant statistical differences were noted between the TV Ad35+ group, the vector control group, NC-V, and the main control group, NC-T4 (ANOVA) Boosting with Ad26-TBS at week 16 did not result in decreased bacterial burden by week 28 compared to all other groups in the study (p = 0.14, ANOVA)
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pone.0127907.g006: Lung bacterial burden as measured by colony forming units (CFU) over time.At week -2, mice were infected via aerosol with M.tb at exponential phase of growth. One day following infection, 5 mice from the NC-IU group were sacrificed to determine the infection load. Following CFU enumeration at week 0, mice were randomized and treatment with R, H and Z was initiated for all groups except the NC-IU group as depicted in Fig 1. Mice from the chronically infected group, NC-IU, became progressively moribund and were sacrificed at week 12. At times indicated, immunotherapy with Ad35-TBS and Ad26-TBS were administered via intramuscular injections to the TV Ad35+ and TV Ad26+ animals, respectively. Animals in the NC-V and TV Ad26- received empty Ad35 and Ad26 vectors at the same immunotherapy time points. At week 16, treatment was truncated for mice in the NC-T4, TV Ad35+, NC-V, TV Ad26+ and TV Ad26-. Animals in the PC group received the full treatment through to week 24. CFU enumeration was conducted every 4 weeks following treatment cessation to monitor relapse in all groups that underwent therapy. The lower limit of detection was set at 10 CFU per total lung. Graph depicts the mean CFU value with standard deviation (n = 23, weeks 28 and 36). At all time points measured, no significant statistical differences were noted between the TV Ad35+ group, the vector control group, NC-V, and the main control group, NC-T4 (ANOVA) Boosting with Ad26-TBS at week 16 did not result in decreased bacterial burden by week 28 compared to all other groups in the study (p = 0.14, ANOVA)

Mentions: To monitor the number of colony forming units (CFU) over time, mice were sacrificed at each time point indicated in Fig 1 and Table 1. On the first day of the experiment (week -2), BALB/c mice were infected via aerosol with an exponential phase culture of M.tb H37Rv. One day later, mice were sacrificed to determine the bacterial burden at the start of infection and the mean lung CFU counts (+/- SD) were found to be 2.99 +/- 0.26 log10. Two weeks later, the number of CFUs increased to 6.69 +/- 0.02 log10 by week 0. At this time (designated week 0), animals were divided into groups that received the initiation phase of the treatment with RHZ (PC, NC-T4, TV Ad35+ and NC-V) and those that were left untreated (NC-IU). For the NC-IU animals, the CFU counts plateaued as infection entered the chronic phase and dropped slightly to 5.83 +/- 0.16 log10 by week 12 when the animals became moribund and were sacrificed (Fig 6).


Immunogenicity without Efficacy of an Adenoviral Tuberculosis Vaccine in a Stringent Mouse Model for Immunotherapy during Treatment.

Alyahya SA, Nolan ST, Smith CM, Bishai WR, Sadoff J, Lamichhane G - PLoS ONE (2015)

Lung bacterial burden as measured by colony forming units (CFU) over time.At week -2, mice were infected via aerosol with M.tb at exponential phase of growth. One day following infection, 5 mice from the NC-IU group were sacrificed to determine the infection load. Following CFU enumeration at week 0, mice were randomized and treatment with R, H and Z was initiated for all groups except the NC-IU group as depicted in Fig 1. Mice from the chronically infected group, NC-IU, became progressively moribund and were sacrificed at week 12. At times indicated, immunotherapy with Ad35-TBS and Ad26-TBS were administered via intramuscular injections to the TV Ad35+ and TV Ad26+ animals, respectively. Animals in the NC-V and TV Ad26- received empty Ad35 and Ad26 vectors at the same immunotherapy time points. At week 16, treatment was truncated for mice in the NC-T4, TV Ad35+, NC-V, TV Ad26+ and TV Ad26-. Animals in the PC group received the full treatment through to week 24. CFU enumeration was conducted every 4 weeks following treatment cessation to monitor relapse in all groups that underwent therapy. The lower limit of detection was set at 10 CFU per total lung. Graph depicts the mean CFU value with standard deviation (n = 23, weeks 28 and 36). At all time points measured, no significant statistical differences were noted between the TV Ad35+ group, the vector control group, NC-V, and the main control group, NC-T4 (ANOVA) Boosting with Ad26-TBS at week 16 did not result in decreased bacterial burden by week 28 compared to all other groups in the study (p = 0.14, ANOVA)
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pone.0127907.g006: Lung bacterial burden as measured by colony forming units (CFU) over time.At week -2, mice were infected via aerosol with M.tb at exponential phase of growth. One day following infection, 5 mice from the NC-IU group were sacrificed to determine the infection load. Following CFU enumeration at week 0, mice were randomized and treatment with R, H and Z was initiated for all groups except the NC-IU group as depicted in Fig 1. Mice from the chronically infected group, NC-IU, became progressively moribund and were sacrificed at week 12. At times indicated, immunotherapy with Ad35-TBS and Ad26-TBS were administered via intramuscular injections to the TV Ad35+ and TV Ad26+ animals, respectively. Animals in the NC-V and TV Ad26- received empty Ad35 and Ad26 vectors at the same immunotherapy time points. At week 16, treatment was truncated for mice in the NC-T4, TV Ad35+, NC-V, TV Ad26+ and TV Ad26-. Animals in the PC group received the full treatment through to week 24. CFU enumeration was conducted every 4 weeks following treatment cessation to monitor relapse in all groups that underwent therapy. The lower limit of detection was set at 10 CFU per total lung. Graph depicts the mean CFU value with standard deviation (n = 23, weeks 28 and 36). At all time points measured, no significant statistical differences were noted between the TV Ad35+ group, the vector control group, NC-V, and the main control group, NC-T4 (ANOVA) Boosting with Ad26-TBS at week 16 did not result in decreased bacterial burden by week 28 compared to all other groups in the study (p = 0.14, ANOVA)
Mentions: To monitor the number of colony forming units (CFU) over time, mice were sacrificed at each time point indicated in Fig 1 and Table 1. On the first day of the experiment (week -2), BALB/c mice were infected via aerosol with an exponential phase culture of M.tb H37Rv. One day later, mice were sacrificed to determine the bacterial burden at the start of infection and the mean lung CFU counts (+/- SD) were found to be 2.99 +/- 0.26 log10. Two weeks later, the number of CFUs increased to 6.69 +/- 0.02 log10 by week 0. At this time (designated week 0), animals were divided into groups that received the initiation phase of the treatment with RHZ (PC, NC-T4, TV Ad35+ and NC-V) and those that were left untreated (NC-IU). For the NC-IU animals, the CFU counts plateaued as infection entered the chronic phase and dropped slightly to 5.83 +/- 0.16 log10 by week 12 when the animals became moribund and were sacrificed (Fig 6).

Bottom Line: Even though immunotherapy resulted in strong splenic IFN-γ responses, no effect on bacterial replication in the lungs was seen.Multiplex assay analysis of lung samples revealed the absence of cytokine augmentation such as IFN-γ, TNF-α and IL-2, suggesting that immunization failed to induce immunity in the lungs.The results obtained from our study raise questions regarding the traits of protective TB immunity that are relevant for the development of future immunotherapeutic and post-exposure vaccination strategies.

View Article: PubMed Central - PubMed

Affiliation: Crucell Holland B.V., Janssen Infectious Diseases and Vaccines, Leiden, The Netherlands.

ABSTRACT
To investigate if bacterial persistence during TB drug treatment could be overcome by modulation of host immunity, we adapted a clinically-relevant model developed for the evaluation of new drugs and examined if immunotherapy with two adenoviral vaccines, Ad35-TBS (AERAS-402) and Ad26-TBS, could shorten therapy in mice. Even though immunotherapy resulted in strong splenic IFN-γ responses, no effect on bacterial replication in the lungs was seen. Multiplex assay analysis of lung samples revealed the absence of cytokine augmentation such as IFN-γ, TNF-α and IL-2, suggesting that immunization failed to induce immunity in the lungs. In this model, we show that IFN-γ levels were not associated with protection against disease relapse. The results obtained from our study raise questions regarding the traits of protective TB immunity that are relevant for the development of future immunotherapeutic and post-exposure vaccination strategies.

No MeSH data available.


Related in: MedlinePlus