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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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Correlations of disease along the infection phase.Thorax radiology, bacterial burden, and hilar LN pathology correlate significantly with lung PA. Loss of total body weight (wasting), and C-reactive protein (CRP) levels and decreasing mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) as measures of systemic inflammation, are highly significant correlates of disease in this high dose challenge model for TB vaccine evaluation. Parameters are plotted per individual (with colouring as indicated in the legend to Figure 2 on group colouring) against lung PA for CXR scores at autopsy (A), CFU counts from lung homogenates (B), hilar LN involvement (C), disseminated extra-thoracic lesions (D), and against total pathology (the sum of lung, hilar LN and extra-thoracic PA scores) for relative change in body weight (E), change in CRP (F), change in MCV (G) and in MCH (H). Spearman's rho (Rs) as correlation factor and p-value are indicated. (AU for arbitrary units.)
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pone-0005264-g004: Correlations of disease along the infection phase.Thorax radiology, bacterial burden, and hilar LN pathology correlate significantly with lung PA. Loss of total body weight (wasting), and C-reactive protein (CRP) levels and decreasing mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) as measures of systemic inflammation, are highly significant correlates of disease in this high dose challenge model for TB vaccine evaluation. Parameters are plotted per individual (with colouring as indicated in the legend to Figure 2 on group colouring) against lung PA for CXR scores at autopsy (A), CFU counts from lung homogenates (B), hilar LN involvement (C), disseminated extra-thoracic lesions (D), and against total pathology (the sum of lung, hilar LN and extra-thoracic PA scores) for relative change in body weight (E), change in CRP (F), change in MCV (G) and in MCH (H). Spearman's rho (Rs) as correlation factor and p-value are indicated. (AU for arbitrary units.)

Mentions: Using a predefined arbitrary gross pathology (PA) scoring system for TB-associated lesions at autopsy, partial protection against challenge was demonstrated in all vaccine groups. Summed PA scores were 142, 63.5, 39 and 61 for non-vaccinated, BCG, BCG/MVA and SO2 groups, respectively (Table 2). As depicted in Figure 3A and 3C similar trends of reduced pathology after vaccination were observed for both lung PA and disseminated disease by extra-thoracic PA, respectively. The reduction in macroscopic lung PA was statistically signficant (p<0.05) for both BCG/MVA and SO2 treatment and approached significance (0.1>p>0.05) for BCG alone. Hilar LN pathology was particularly reduced after BCG/MVA vaccination (Figure 3B). Hilar LN involvement and extra-thoracic PA showed relatively weak correlation with gross lung PA at autopsy as calculated by non-parametric Spearman's rho (Rs) (Figure 4C and 4D, respectively).


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)

Correlations of disease along the infection phase.Thorax radiology, bacterial burden, and hilar LN pathology correlate significantly with lung PA. Loss of total body weight (wasting), and C-reactive protein (CRP) levels and decreasing mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) as measures of systemic inflammation, are highly significant correlates of disease in this high dose challenge model for TB vaccine evaluation. Parameters are plotted per individual (with colouring as indicated in the legend to Figure 2 on group colouring) against lung PA for CXR scores at autopsy (A), CFU counts from lung homogenates (B), hilar LN involvement (C), disseminated extra-thoracic lesions (D), and against total pathology (the sum of lung, hilar LN and extra-thoracic PA scores) for relative change in body weight (E), change in CRP (F), change in MCV (G) and in MCH (H). Spearman's rho (Rs) as correlation factor and p-value are indicated. (AU for arbitrary units.)
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005264-g004: Correlations of disease along the infection phase.Thorax radiology, bacterial burden, and hilar LN pathology correlate significantly with lung PA. Loss of total body weight (wasting), and C-reactive protein (CRP) levels and decreasing mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) as measures of systemic inflammation, are highly significant correlates of disease in this high dose challenge model for TB vaccine evaluation. Parameters are plotted per individual (with colouring as indicated in the legend to Figure 2 on group colouring) against lung PA for CXR scores at autopsy (A), CFU counts from lung homogenates (B), hilar LN involvement (C), disseminated extra-thoracic lesions (D), and against total pathology (the sum of lung, hilar LN and extra-thoracic PA scores) for relative change in body weight (E), change in CRP (F), change in MCV (G) and in MCH (H). Spearman's rho (Rs) as correlation factor and p-value are indicated. (AU for arbitrary units.)
Mentions: Using a predefined arbitrary gross pathology (PA) scoring system for TB-associated lesions at autopsy, partial protection against challenge was demonstrated in all vaccine groups. Summed PA scores were 142, 63.5, 39 and 61 for non-vaccinated, BCG, BCG/MVA and SO2 groups, respectively (Table 2). As depicted in Figure 3A and 3C similar trends of reduced pathology after vaccination were observed for both lung PA and disseminated disease by extra-thoracic PA, respectively. The reduction in macroscopic lung PA was statistically signficant (p<0.05) for both BCG/MVA and SO2 treatment and approached significance (0.1>p>0.05) for BCG alone. Hilar LN pathology was particularly reduced after BCG/MVA vaccination (Figure 3B). Hilar LN involvement and extra-thoracic PA showed relatively weak correlation with gross lung PA at autopsy as calculated by non-parametric Spearman's rho (Rs) (Figure 4C and 4D, respectively).

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