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Intranasal mucosal boosting with an adenovirus-vectored vaccine markedly enhances the protection of BCG-primed guinea pigs against pulmonary tuberculosis.

Xing Z, McFarland CT, Sallenave JM, Izzo A, Wang J, McMurray DN - PLoS ONE (2009)

Bottom Line: In separate studies, the long-term disease outcome of infected animals was monitored until the termination of this study.Immunization with Ad vaccine alone had minimal beneficial effects.Immunization with BCG alone and BCG prime-Ad vaccine boost regimens significantly reduced the level of M.tb infection in the tissues to a similar extent.

View Article: PubMed Central - PubMed

Affiliation: Centre for Gene Therapeutics, MG DeGroote Institute for Infectious Disease Research, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. xingz@mcmaster.ca

ABSTRACT

Background: Recombinant adenovirus-vectored (Ad) tuberculosis (TB) vaccine platform has demonstrated great potential to be used either as a stand-alone or a boost vaccine in murine models. However, Ad TB vaccine remains to be evaluated in a more relevant and sensitive guinea pig model of pulmonary TB. Many vaccine candidates shown to be effective in murine models have subsequently failed to pass the test in guinea pig models.

Methods and findings: Specific pathogen-free guinea pigs were immunized with BCG, AdAg85A intranasally (i.n), AdAg85A intramuscularly (i.m), BCG boosted with AdAg85A i.n, BCG boosted with AdAg85A i.m, or treated only with saline. The animals were then infected by a low-dose aerosol of M. tuberculosis (M.tb). At the specified times, the animals were sacrificed and the levels of infection in the lung and spleen were assessed. In separate studies, the long-term disease outcome of infected animals was monitored until the termination of this study. Immunization with Ad vaccine alone had minimal beneficial effects. Immunization with BCG alone and BCG prime-Ad vaccine boost regimens significantly reduced the level of M.tb infection in the tissues to a similar extent. However, while BCG alone prolonged the survival of infected guinea pigs, the majority of BCG-immunized animals succumbed by 53 weeks post-M.tb challenge. In contrast, intranasal or intramuscular Ad vaccine boosting of BCG-primed animals markedly improved the survival rate with 60% of BCG/Ad i.n- and 40% of BCG/Ad i.m-immunized guinea pigs still surviving by 74 weeks post-aerosol challenge.

Conclusions: Boosting, particularly via the intranasal mucosal route, with AdAg85A vaccine is able to significantly enhance the long-term survival of BCG-primed guinea pigs following pulmonary M.tb challenge. Our results thus support further evaluation of this viral-vectored TB vaccine in clinical trials.

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Comparison of average body weight changes at ten weeks post-M.tb challenge.Groups of guinea pigs were treated as depicted in Fig. 1B and body weight changes were monitored on a weekly basis. The data are the average body weight±SEM of each treatment group (eight animals per group) recorded at 10 weeks post-M.tb challenge prior to the occurrence of mortality in any treatment groups. **p≤0.01, *p≤0.05 compared to saline control.
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pone-0005856-g003: Comparison of average body weight changes at ten weeks post-M.tb challenge.Groups of guinea pigs were treated as depicted in Fig. 1B and body weight changes were monitored on a weekly basis. The data are the average body weight±SEM of each treatment group (eight animals per group) recorded at 10 weeks post-M.tb challenge prior to the occurrence of mortality in any treatment groups. **p≤0.01, *p≤0.05 compared to saline control.

Mentions: As the bacterial loads in the tissue of guinea pig models may not adequately predict the protective efficacy of a test vaccine [19], in separate studies the long-term disease outcome was monitored following immunization and low dose M.tb aerosol challenge in a separate study. By the end of first 10 weeks post-infection, unimmunized guinea pigs already began to display deteriorating overall health conditions including much lower average body weight compared to the immunized groups (Fig. 3; BCG p = 0.008, BCG/Ad i.n p = 0.006 and BCG/Ad i.m p = 0.03 compared to saline control).


Intranasal mucosal boosting with an adenovirus-vectored vaccine markedly enhances the protection of BCG-primed guinea pigs against pulmonary tuberculosis.

Xing Z, McFarland CT, Sallenave JM, Izzo A, Wang J, McMurray DN - PLoS ONE (2009)

Comparison of average body weight changes at ten weeks post-M.tb challenge.Groups of guinea pigs were treated as depicted in Fig. 1B and body weight changes were monitored on a weekly basis. The data are the average body weight±SEM of each treatment group (eight animals per group) recorded at 10 weeks post-M.tb challenge prior to the occurrence of mortality in any treatment groups. **p≤0.01, *p≤0.05 compared to saline control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2689939&req=5

pone-0005856-g003: Comparison of average body weight changes at ten weeks post-M.tb challenge.Groups of guinea pigs were treated as depicted in Fig. 1B and body weight changes were monitored on a weekly basis. The data are the average body weight±SEM of each treatment group (eight animals per group) recorded at 10 weeks post-M.tb challenge prior to the occurrence of mortality in any treatment groups. **p≤0.01, *p≤0.05 compared to saline control.
Mentions: As the bacterial loads in the tissue of guinea pig models may not adequately predict the protective efficacy of a test vaccine [19], in separate studies the long-term disease outcome was monitored following immunization and low dose M.tb aerosol challenge in a separate study. By the end of first 10 weeks post-infection, unimmunized guinea pigs already began to display deteriorating overall health conditions including much lower average body weight compared to the immunized groups (Fig. 3; BCG p = 0.008, BCG/Ad i.n p = 0.006 and BCG/Ad i.m p = 0.03 compared to saline control).

Bottom Line: In separate studies, the long-term disease outcome of infected animals was monitored until the termination of this study.Immunization with Ad vaccine alone had minimal beneficial effects.Immunization with BCG alone and BCG prime-Ad vaccine boost regimens significantly reduced the level of M.tb infection in the tissues to a similar extent.

View Article: PubMed Central - PubMed

Affiliation: Centre for Gene Therapeutics, MG DeGroote Institute for Infectious Disease Research, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. xingz@mcmaster.ca

ABSTRACT

Background: Recombinant adenovirus-vectored (Ad) tuberculosis (TB) vaccine platform has demonstrated great potential to be used either as a stand-alone or a boost vaccine in murine models. However, Ad TB vaccine remains to be evaluated in a more relevant and sensitive guinea pig model of pulmonary TB. Many vaccine candidates shown to be effective in murine models have subsequently failed to pass the test in guinea pig models.

Methods and findings: Specific pathogen-free guinea pigs were immunized with BCG, AdAg85A intranasally (i.n), AdAg85A intramuscularly (i.m), BCG boosted with AdAg85A i.n, BCG boosted with AdAg85A i.m, or treated only with saline. The animals were then infected by a low-dose aerosol of M. tuberculosis (M.tb). At the specified times, the animals were sacrificed and the levels of infection in the lung and spleen were assessed. In separate studies, the long-term disease outcome of infected animals was monitored until the termination of this study. Immunization with Ad vaccine alone had minimal beneficial effects. Immunization with BCG alone and BCG prime-Ad vaccine boost regimens significantly reduced the level of M.tb infection in the tissues to a similar extent. However, while BCG alone prolonged the survival of infected guinea pigs, the majority of BCG-immunized animals succumbed by 53 weeks post-M.tb challenge. In contrast, intranasal or intramuscular Ad vaccine boosting of BCG-primed animals markedly improved the survival rate with 60% of BCG/Ad i.n- and 40% of BCG/Ad i.m-immunized guinea pigs still surviving by 74 weeks post-aerosol challenge.

Conclusions: Boosting, particularly via the intranasal mucosal route, with AdAg85A vaccine is able to significantly enhance the long-term survival of BCG-primed guinea pigs following pulmonary M.tb challenge. Our results thus support further evaluation of this viral-vectored TB vaccine in clinical trials.

Show MeSH
Related in: MedlinePlus