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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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Evaluation of clinical measures along the infection phase.The BCG/MVA.85A regime and SO2 vaccination in comparison to non-vaccinated controls show significant protection from TB-associated wasting disease and systemic inflammation. Individual scores and group medians are plotted for relative change in body weight from start to end of the infection phase (A), change in C-reactive protein (CRP) levels (B), in mean corpuscular volume (MCV) (C), and in mean corpuscular hemoglobin (MCH) (D). For legends of colouring and symbols see legend to Figure 2.
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pone-0005264-g005: Evaluation of clinical measures along the infection phase.The BCG/MVA.85A regime and SO2 vaccination in comparison to non-vaccinated controls show significant protection from TB-associated wasting disease and systemic inflammation. Individual scores and group medians are plotted for relative change in body weight from start to end of the infection phase (A), change in C-reactive protein (CRP) levels (B), in mean corpuscular volume (MCV) (C), and in mean corpuscular hemoglobin (MCH) (D). For legends of colouring and symbols see legend to Figure 2.

Mentions: Progressive tuberculosis in man is hallmarked by wasting disease and inflammation. Therefore, in this monkey experiment we measured changes in total body weight and several markers of systemic inflammation prior to and after infectious challenge. Wasting was reflected in the non-vaccinated controls by a (relative) loss of weight from pre-infection to the autopsy timepoint (Figure 5A). This weight loss was reversed by vaccination, and statistically significant improvement in comparison to non-vaccinated, but not to BCG controls was obtained for both BCG/MVA and SO2 (Figure 5A).


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)

Evaluation of clinical measures along the infection phase.The BCG/MVA.85A regime and SO2 vaccination in comparison to non-vaccinated controls show significant protection from TB-associated wasting disease and systemic inflammation. Individual scores and group medians are plotted for relative change in body weight from start to end of the infection phase (A), change in C-reactive protein (CRP) levels (B), in mean corpuscular volume (MCV) (C), and in mean corpuscular hemoglobin (MCH) (D). For legends of colouring and symbols see legend to Figure 2.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005264-g005: Evaluation of clinical measures along the infection phase.The BCG/MVA.85A regime and SO2 vaccination in comparison to non-vaccinated controls show significant protection from TB-associated wasting disease and systemic inflammation. Individual scores and group medians are plotted for relative change in body weight from start to end of the infection phase (A), change in C-reactive protein (CRP) levels (B), in mean corpuscular volume (MCV) (C), and in mean corpuscular hemoglobin (MCH) (D). For legends of colouring and symbols see legend to Figure 2.
Mentions: Progressive tuberculosis in man is hallmarked by wasting disease and inflammation. Therefore, in this monkey experiment we measured changes in total body weight and several markers of systemic inflammation prior to and after infectious challenge. Wasting was reflected in the non-vaccinated controls by a (relative) loss of weight from pre-infection to the autopsy timepoint (Figure 5A). This weight loss was reversed by vaccination, and statistically significant improvement in comparison to non-vaccinated, but not to BCG controls was obtained for both BCG/MVA and SO2 (Figure 5A).

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