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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-vaccination.Both the SO2 primary and the MVA.85A booster vaccine are immunogenic in rhesus macaques. Antigen-specific IFNγ secretion was measured after 3 days of in vitro stimulation of fresh peripheral blood lymphocytes along the vaccination phase. PPD-specific IFNγ secretion is depicted as group mean responses (+standard error) in time (A), and as individual responses with medians at the peak of the mean group response (B). Similarly, results upon stimulation with recombinant Ag85A are displayed as group means (+standard error) in time (C), and as individual responses (with medians) at peak (D), respectively. Colouring of group medians (panels A and C) is representing non-vaccinated controls in blue, BCG only in green, BCG/MVA.85A in magenta, and SO2 vaccination in red; group colouring is maintained throughout the paper for comparibility of data. Dot plots representing individual animals (panels B and D) are consistently coloured as follows: animals per treatment group were ranked from highest to lowest total gross pathology score (sum of lung, hilar LN and extra-thoracic scores) and then assigned the colours: blue, green, magenta, red, brown, black, respectively; individual colouring is maintained throughout for comparability. P-values are relative to non-vaccinated control treatment and represented under the x-axis by symbols as follows: ▪ for 0.1>p≥0.05, ★ for 0.05>p≥0.01, ★★ for 0.01>p≥0.001.
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pone-0005264-g002: Mycobacterium-specific IFNγ secretion post-vaccination.Both the SO2 primary and the MVA.85A booster vaccine are immunogenic in rhesus macaques. Antigen-specific IFNγ secretion was measured after 3 days of in vitro stimulation of fresh peripheral blood lymphocytes along the vaccination phase. PPD-specific IFNγ secretion is depicted as group mean responses (+standard error) in time (A), and as individual responses with medians at the peak of the mean group response (B). Similarly, results upon stimulation with recombinant Ag85A are displayed as group means (+standard error) in time (C), and as individual responses (with medians) at peak (D), respectively. Colouring of group medians (panels A and C) is representing non-vaccinated controls in blue, BCG only in green, BCG/MVA.85A in magenta, and SO2 vaccination in red; group colouring is maintained throughout the paper for comparibility of data. Dot plots representing individual animals (panels B and D) are consistently coloured as follows: animals per treatment group were ranked from highest to lowest total gross pathology score (sum of lung, hilar LN and extra-thoracic scores) and then assigned the colours: blue, green, magenta, red, brown, black, respectively; individual colouring is maintained throughout for comparability. P-values are relative to non-vaccinated control treatment and represented under the x-axis by symbols as follows: ▪ for 0.1>p≥0.05, ★ for 0.05>p≥0.01, ★★ for 0.01>p≥0.001.

Mentions: Following vaccination no clinically significant changes in behaviour, weight or parameters of hematology and clinical chemistry were evident in any group (data not shown). Mild swelling and redness occurred at the MVA injection site with self-limiting vesicle and crust formation not requiring medical attention and reminiscent of observations in human MVA vaccination [7]. All vaccinated groups, but not non-vaccinated controls, showed increased IFNγ secretion against M. tuberculosis purified protein derivative (PPD); responses were maximal at week 9 post-primary immunisation and highest in the SO2 group (Figure 2A and 2B). Antigen 85A-specific IFNγ secretion increased after booster immunisation with MVA.85A only (Figure 2C and 2D).


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-vaccination.Both the SO2 primary and the MVA.85A booster vaccine are immunogenic in rhesus macaques. Antigen-specific IFNγ secretion was measured after 3 days of in vitro stimulation of fresh peripheral blood lymphocytes along the vaccination phase. PPD-specific IFNγ secretion is depicted as group mean responses (+standard error) in time (A), and as individual responses with medians at the peak of the mean group response (B). Similarly, results upon stimulation with recombinant Ag85A are displayed as group means (+standard error) in time (C), and as individual responses (with medians) at peak (D), respectively. Colouring of group medians (panels A and C) is representing non-vaccinated controls in blue, BCG only in green, BCG/MVA.85A in magenta, and SO2 vaccination in red; group colouring is maintained throughout the paper for comparibility of data. Dot plots representing individual animals (panels B and D) are consistently coloured as follows: animals per treatment group were ranked from highest to lowest total gross pathology score (sum of lung, hilar LN and extra-thoracic scores) and then assigned the colours: blue, green, magenta, red, brown, black, respectively; individual colouring is maintained throughout for comparability. P-values are relative to non-vaccinated control treatment and represented under the x-axis by symbols as follows: ▪ for 0.1>p≥0.05, ★ for 0.05>p≥0.01, ★★ for 0.01>p≥0.001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2666807&req=5

pone-0005264-g002: Mycobacterium-specific IFNγ secretion post-vaccination.Both the SO2 primary and the MVA.85A booster vaccine are immunogenic in rhesus macaques. Antigen-specific IFNγ secretion was measured after 3 days of in vitro stimulation of fresh peripheral blood lymphocytes along the vaccination phase. PPD-specific IFNγ secretion is depicted as group mean responses (+standard error) in time (A), and as individual responses with medians at the peak of the mean group response (B). Similarly, results upon stimulation with recombinant Ag85A are displayed as group means (+standard error) in time (C), and as individual responses (with medians) at peak (D), respectively. Colouring of group medians (panels A and C) is representing non-vaccinated controls in blue, BCG only in green, BCG/MVA.85A in magenta, and SO2 vaccination in red; group colouring is maintained throughout the paper for comparibility of data. Dot plots representing individual animals (panels B and D) are consistently coloured as follows: animals per treatment group were ranked from highest to lowest total gross pathology score (sum of lung, hilar LN and extra-thoracic scores) and then assigned the colours: blue, green, magenta, red, brown, black, respectively; individual colouring is maintained throughout for comparability. P-values are relative to non-vaccinated control treatment and represented under the x-axis by symbols as follows: ▪ for 0.1>p≥0.05, ★ for 0.05>p≥0.01, ★★ for 0.01>p≥0.001.
Mentions: Following vaccination no clinically significant changes in behaviour, weight or parameters of hematology and clinical chemistry were evident in any group (data not shown). Mild swelling and redness occurred at the MVA injection site with self-limiting vesicle and crust formation not requiring medical attention and reminiscent of observations in human MVA vaccination [7]. All vaccinated groups, but not non-vaccinated controls, showed increased IFNγ secretion against M. tuberculosis purified protein derivative (PPD); responses were maximal at week 9 post-primary immunisation and highest in the SO2 group (Figure 2A and 2B). Antigen 85A-specific IFNγ secretion increased after booster immunisation with MVA.85A only (Figure 2C and 2D).

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