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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

Immunogenicity of Ad35-TBS and Ad26-TBS immunotherapy.At week 4, baseline IFN-γ production to pooled peptides covering the whole sequence of Ag85A, Ag85B and TB10.4 were measured by ELISpot prior to randomization (refer to Fig 1). At this time point, the values between the NC-T4 and TV Ad35+ are identical. Following randomization, animals in the TV Ad35+ group received immunotherapy at weeks 4 and 8 with 1010 viral particles of Ad35-TBS intramuscularly. At week 16, baseline immune responses were measured in the TV Ad35+ group prior to randomization into TV Ad26+ and TV Ad26- groups. The TV Ad26+ animals then received heterologous boosting with 1010 viral particles of Ad26-TBS at week 16 whilst the TV Ad26- received empty Ad26 vector as control. p-values were calculated two weeks after each immunotherapy (weeks 6 and 10) and are detailed in Table 2 (ANOVA followed by Tukey’s multiple comparisons test, n = 5 at each time point for all groups). Lines depict geometric mean. No significant differences were observed following Ad26-TBS boosting at week 16 for all groups (NS = not significant, t-test). SFU = splenocyte forming units.
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pone.0127907.g002: Immunogenicity of Ad35-TBS and Ad26-TBS immunotherapy.At week 4, baseline IFN-γ production to pooled peptides covering the whole sequence of Ag85A, Ag85B and TB10.4 were measured by ELISpot prior to randomization (refer to Fig 1). At this time point, the values between the NC-T4 and TV Ad35+ are identical. Following randomization, animals in the TV Ad35+ group received immunotherapy at weeks 4 and 8 with 1010 viral particles of Ad35-TBS intramuscularly. At week 16, baseline immune responses were measured in the TV Ad35+ group prior to randomization into TV Ad26+ and TV Ad26- groups. The TV Ad26+ animals then received heterologous boosting with 1010 viral particles of Ad26-TBS at week 16 whilst the TV Ad26- received empty Ad26 vector as control. p-values were calculated two weeks after each immunotherapy (weeks 6 and 10) and are detailed in Table 2 (ANOVA followed by Tukey’s multiple comparisons test, n = 5 at each time point for all groups). Lines depict geometric mean. No significant differences were observed following Ad26-TBS boosting at week 16 for all groups (NS = not significant, t-test). SFU = splenocyte forming units.

Mentions: In order to determine the immune response to vaccination, ELISpot analysis was conducted immediately prior to and two weeks after vaccinations with Ad35-TBS, Ad26-TBS and their respective empty vector controls (Fig 1). Considering the initial TB infection to be the priming immune response, we observed that immunotherapy with Ad35-TBS at weeks 4 and 8 boosted the immune response to vaccine antigens by week 10 compared to the unvaccinated treated control, NC-T4, as measured by splenocyte IFN-γ production to pooled peptide antigens (Fig 2, Table 2). Heterologous boosting with Ad26-TBS however did not augment the immune response further compared to week 16. Nonetheless, a significant difference to the empty vector control group TV Ad26- was detected, suggesting that boosting maintained the heightened responses achieved by the previous two immunizations with Ad35-TBS (Fig 2, Table 2). Due to the similarity in responses between the control groups, only data from the main control group NC-T4 is presented in Fig 2. Data from all study groups for all time points can be found in S1 Fig.


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)

Immunogenicity of Ad35-TBS and Ad26-TBS immunotherapy.At week 4, baseline IFN-γ production to pooled peptides covering the whole sequence of Ag85A, Ag85B and TB10.4 were measured by ELISpot prior to randomization (refer to Fig 1). At this time point, the values between the NC-T4 and TV Ad35+ are identical. Following randomization, animals in the TV Ad35+ group received immunotherapy at weeks 4 and 8 with 1010 viral particles of Ad35-TBS intramuscularly. At week 16, baseline immune responses were measured in the TV Ad35+ group prior to randomization into TV Ad26+ and TV Ad26- groups. The TV Ad26+ animals then received heterologous boosting with 1010 viral particles of Ad26-TBS at week 16 whilst the TV Ad26- received empty Ad26 vector as control. p-values were calculated two weeks after each immunotherapy (weeks 6 and 10) and are detailed in Table 2 (ANOVA followed by Tukey’s multiple comparisons test, n = 5 at each time point for all groups). Lines depict geometric mean. No significant differences were observed following Ad26-TBS boosting at week 16 for all groups (NS = not significant, t-test). SFU = splenocyte forming units.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4440646&req=5

pone.0127907.g002: Immunogenicity of Ad35-TBS and Ad26-TBS immunotherapy.At week 4, baseline IFN-γ production to pooled peptides covering the whole sequence of Ag85A, Ag85B and TB10.4 were measured by ELISpot prior to randomization (refer to Fig 1). At this time point, the values between the NC-T4 and TV Ad35+ are identical. Following randomization, animals in the TV Ad35+ group received immunotherapy at weeks 4 and 8 with 1010 viral particles of Ad35-TBS intramuscularly. At week 16, baseline immune responses were measured in the TV Ad35+ group prior to randomization into TV Ad26+ and TV Ad26- groups. The TV Ad26+ animals then received heterologous boosting with 1010 viral particles of Ad26-TBS at week 16 whilst the TV Ad26- received empty Ad26 vector as control. p-values were calculated two weeks after each immunotherapy (weeks 6 and 10) and are detailed in Table 2 (ANOVA followed by Tukey’s multiple comparisons test, n = 5 at each time point for all groups). Lines depict geometric mean. No significant differences were observed following Ad26-TBS boosting at week 16 for all groups (NS = not significant, t-test). SFU = splenocyte forming units.
Mentions: In order to determine the immune response to vaccination, ELISpot analysis was conducted immediately prior to and two weeks after vaccinations with Ad35-TBS, Ad26-TBS and their respective empty vector controls (Fig 1). Considering the initial TB infection to be the priming immune response, we observed that immunotherapy with Ad35-TBS at weeks 4 and 8 boosted the immune response to vaccine antigens by week 10 compared to the unvaccinated treated control, NC-T4, as measured by splenocyte IFN-γ production to pooled peptide antigens (Fig 2, Table 2). Heterologous boosting with Ad26-TBS however did not augment the immune response further compared to week 16. Nonetheless, a significant difference to the empty vector control group TV Ad26- was detected, suggesting that boosting maintained the heightened responses achieved by the previous two immunizations with Ad35-TBS (Fig 2, Table 2). Due to the similarity in responses between the control groups, only data from the main control group NC-T4 is presented in Fig 2. Data from all study groups for all time points can be found in S1 Fig.

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