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MVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaques.

Verreck FA, Vervenne RA, Kondova I, van Kralingen KW, Remarque EJ, Braskamp G, van der Werff NM, Kersbergen A, Ottenhoff TH, Heidt PJ, Gilbert SC, Gicquel B, Hill AV, Martin C, McShane H, Thomas AW - PLoS ONE (2009)

Bottom Line: Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses.MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls.Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands. verreck@bprc.nl

ABSTRACT

Background: Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection.

Methods and findings: Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A), and attenuated M. tuberculosis with a disrupted phoP gene (SO2) as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses. Antigen 85A-specific IFNgamma secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNgamma levels post-infection as the strongest immunocorrelate for protection (spearman's rho: -0.60).

Conclusions: Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates.

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Immune correlations of disease.Maximal PPD-specific IFNγ levels post-vaccination and maximal Ag85A-specific IFNγ post-infection show significant inverse correlations with TB disease by total gross lesion PA scores. Maximal antigen-specific IFNγ response levels are plotted per individual against total pathology scores (with colouring as indicated in the legend to figure 2 on group colouring) and post-vaccination and post-infection for PPD (A and B, respectively) and Ag85A (C and D, respectively), and for ESAT6-CFP10 fusion protein post-infection only (E).
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pone-0005264-g007: Immune correlations of disease.Maximal PPD-specific IFNγ levels post-vaccination and maximal Ag85A-specific IFNγ post-infection show significant inverse correlations with TB disease by total gross lesion PA scores. Maximal antigen-specific IFNγ response levels are plotted per individual against total pathology scores (with colouring as indicated in the legend to figure 2 on group colouring) and post-vaccination and post-infection for PPD (A and B, respectively) and Ag85A (C and D, respectively), and for ESAT6-CFP10 fusion protein post-infection only (E).

Mentions: For both post-vaccination (pre-infection) and post-infection timepoints coefficients of correlation between individual maximal antigen specfic IFNγ levels and total PA lesion scores were calculated. Maximal PPD specific IFNγ levels post-vaccination (Figures 7A), but not post-infection (Figures 7B), showed a significant and inverse correlation with total PA (Rs = −0.49, p = 0.0140). Contrarily, maximal IFNγ release upon Ag85A stimulation post-infection (Figure 7D), but not post-vaccination (Figure 7C), correlated significantly with disease by total PA lesion score (Rs = −0.60, p = 0.0018). ESAT6/CFP10 specific maximal IFNγ secretion, which was monitored in the post-infection phase only, did not correlate significantly with total PA at autopsy (Figure 7E).


MVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaques.

Verreck FA, Vervenne RA, Kondova I, van Kralingen KW, Remarque EJ, Braskamp G, van der Werff NM, Kersbergen A, Ottenhoff TH, Heidt PJ, Gilbert SC, Gicquel B, Hill AV, Martin C, McShane H, Thomas AW - PLoS ONE (2009)

Immune correlations of disease.Maximal PPD-specific IFNγ levels post-vaccination and maximal Ag85A-specific IFNγ post-infection show significant inverse correlations with TB disease by total gross lesion PA scores. Maximal antigen-specific IFNγ response levels are plotted per individual against total pathology scores (with colouring as indicated in the legend to figure 2 on group colouring) and post-vaccination and post-infection for PPD (A and B, respectively) and Ag85A (C and D, respectively), and for ESAT6-CFP10 fusion protein post-infection only (E).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2666807&req=5

pone-0005264-g007: Immune correlations of disease.Maximal PPD-specific IFNγ levels post-vaccination and maximal Ag85A-specific IFNγ post-infection show significant inverse correlations with TB disease by total gross lesion PA scores. Maximal antigen-specific IFNγ response levels are plotted per individual against total pathology scores (with colouring as indicated in the legend to figure 2 on group colouring) and post-vaccination and post-infection for PPD (A and B, respectively) and Ag85A (C and D, respectively), and for ESAT6-CFP10 fusion protein post-infection only (E).
Mentions: For both post-vaccination (pre-infection) and post-infection timepoints coefficients of correlation between individual maximal antigen specfic IFNγ levels and total PA lesion scores were calculated. Maximal PPD specific IFNγ levels post-vaccination (Figures 7A), but not post-infection (Figures 7B), showed a significant and inverse correlation with total PA (Rs = −0.49, p = 0.0140). Contrarily, maximal IFNγ release upon Ag85A stimulation post-infection (Figure 7D), but not post-vaccination (Figure 7C), correlated significantly with disease by total PA lesion score (Rs = −0.60, p = 0.0018). ESAT6/CFP10 specific maximal IFNγ secretion, which was monitored in the post-infection phase only, did not correlate significantly with total PA at autopsy (Figure 7E).

Bottom Line: Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses.MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls.Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands. verreck@bprc.nl

ABSTRACT

Background: Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection.

Methods and findings: Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A), and attenuated M. tuberculosis with a disrupted phoP gene (SO2) as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses. Antigen 85A-specific IFNgamma secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNgamma levels post-infection as the strongest immunocorrelate for protection (spearman's rho: -0.60).

Conclusions: Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates.

Show MeSH
Related in: MedlinePlus