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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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Related in: MedlinePlus

Experimental plan.A schematic diagram illustrating the timelines of vaccination (priming at week 0, boosting at week 9 for group 3 only), infectious challenge, immune monitoring, chest X-ray recording and fixed endpoint/autopsies by study protocol all relative to the 18 weeks immunisation phase or the 17/18 weeks challenge phase.
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pone-0005264-g001: Experimental plan.A schematic diagram illustrating the timelines of vaccination (priming at week 0, boosting at week 9 for group 3 only), infectious challenge, immune monitoring, chest X-ray recording and fixed endpoint/autopsies by study protocol all relative to the 18 weeks immunisation phase or the 17/18 weeks challenge phase.

Mentions: Vaccine treatments, dose and route of injection, and treatment group characteristics, number of animals (n), age and body weight, are summarised in Table 1. A schematic diagram representing the experiment is depicted in Figure 1. In brief, eighteen weeks after primary vaccination, animals were challenged in a single, randomised session by intratracheal instillation of 1000 colony forming units (CFU) of M. tuberculosis Erdman strain. The study plan accommodated a fixed endpoint with pathologic examination after euthanasia (by random sampling) at week 16/17 post-infection. Random stratification of animals over the four treatment groups warranted homogeneous distribution of body weight and age without significant differences between the groups at the start of the experiment (Table 1).


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)

Experimental plan.A schematic diagram illustrating the timelines of vaccination (priming at week 0, boosting at week 9 for group 3 only), infectious challenge, immune monitoring, chest X-ray recording and fixed endpoint/autopsies by study protocol all relative to the 18 weeks immunisation phase or the 17/18 weeks challenge phase.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005264-g001: Experimental plan.A schematic diagram illustrating the timelines of vaccination (priming at week 0, boosting at week 9 for group 3 only), infectious challenge, immune monitoring, chest X-ray recording and fixed endpoint/autopsies by study protocol all relative to the 18 weeks immunisation phase or the 17/18 weeks challenge phase.
Mentions: Vaccine treatments, dose and route of injection, and treatment group characteristics, number of animals (n), age and body weight, are summarised in Table 1. A schematic diagram representing the experiment is depicted in Figure 1. In brief, eighteen weeks after primary vaccination, animals were challenged in a single, randomised session by intratracheal instillation of 1000 colony forming units (CFU) of M. tuberculosis Erdman strain. The study plan accommodated a fixed endpoint with pathologic examination after euthanasia (by random sampling) at week 16/17 post-infection. Random stratification of animals over the four treatment groups warranted homogeneous distribution of body weight and age without significant differences between the groups at the start of the experiment (Table 1).

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