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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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Mycobacterium-specific IFNγ secretion post-infection.Both PPD and ESAT6-CFP10 fusion protein, but not Ag85A, induce relatively high levels of IFNγ from in vitro stimulated fresh PBMC after infectious challenge with M. tuberculosis. Treatment group means (+standard errors) are plotted in time for PPD (A), Ag85A (C) and ESAT6/CFP10 fusion protein (E), and as individual responses (with group medians) at the peak of the mean response as indicated (B, D and F, respectively). For legends of colouring and symbols see legend to Figure 2.
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pone-0005264-g006: Mycobacterium-specific IFNγ secretion post-infection.Both PPD and ESAT6-CFP10 fusion protein, but not Ag85A, induce relatively high levels of IFNγ from in vitro stimulated fresh PBMC after infectious challenge with M. tuberculosis. Treatment group means (+standard errors) are plotted in time for PPD (A), Ag85A (C) and ESAT6/CFP10 fusion protein (E), and as individual responses (with group medians) at the peak of the mean response as indicated (B, D and F, respectively). For legends of colouring and symbols see legend to Figure 2.

Mentions: Specific immune responses in the post-infection phase were monitored by measuring IFNγ secretion levels from fresh PBMC samples stimulated in vitro with PPD, recombinant Ag85A or ESAT6/CFP10 fusion protein. PPD- and ESAT6/CFP10 stimulation revealed highest IFNγ secretion in non-vaccinated controls in general at 6–8 weeks post-infection (Figure 6A and 6B, and 6E and 6F, respectively). In vaccine groups generally these responses were lower than in the non-vaccinated control group. In contrast, post-infection Ag85A specific IFNγ responses were relatively low (in the sub-nanogram range), and on average lower in non-vaccinated controls than in BCG/MVA and SO2 vaccine groups particularly (Fig 6C and 6D).


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)

Mycobacterium-specific IFNγ secretion post-infection.Both PPD and ESAT6-CFP10 fusion protein, but not Ag85A, induce relatively high levels of IFNγ from in vitro stimulated fresh PBMC after infectious challenge with M. tuberculosis. Treatment group means (+standard errors) are plotted in time for PPD (A), Ag85A (C) and ESAT6/CFP10 fusion protein (E), and as individual responses (with group medians) at the peak of the mean response as indicated (B, D and F, respectively). 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-g006: Mycobacterium-specific IFNγ secretion post-infection.Both PPD and ESAT6-CFP10 fusion protein, but not Ag85A, induce relatively high levels of IFNγ from in vitro stimulated fresh PBMC after infectious challenge with M. tuberculosis. Treatment group means (+standard errors) are plotted in time for PPD (A), Ag85A (C) and ESAT6/CFP10 fusion protein (E), and as individual responses (with group medians) at the peak of the mean response as indicated (B, D and F, respectively). For legends of colouring and symbols see legend to Figure 2.
Mentions: Specific immune responses in the post-infection phase were monitored by measuring IFNγ secretion levels from fresh PBMC samples stimulated in vitro with PPD, recombinant Ag85A or ESAT6/CFP10 fusion protein. PPD- and ESAT6/CFP10 stimulation revealed highest IFNγ secretion in non-vaccinated controls in general at 6–8 weeks post-infection (Figure 6A and 6B, and 6E and 6F, respectively). In vaccine groups generally these responses were lower than in the non-vaccinated control group. In contrast, post-infection Ag85A specific IFNγ responses were relatively low (in the sub-nanogram range), and on average lower in non-vaccinated controls than in BCG/MVA and SO2 vaccine groups particularly (Fig 6C and 6D).

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