Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

Minassian, Angela M.; Ronan, Edward O.; Poyntz, Hazel C.; Hill, Adrian V. S.; McShane, Helen

doi:10.1371/journal.pone.0019840

Cited by 39 publications

(51 citation statements)

References 41 publications

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“…The question of BCG persistence has been noted in previous studies in mice [24,25,27,[32][33][34][35], other animal models [23,26] and humans [36,37]. In a similar study using C57BL/6 mice and M. tb challenge [27], spleen protection was reduced by 75%, but in contrast lung immunity was unaffected.…”

Section: Discussionmentioning

confidence: 80%

Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis

Kaveh

García-Pelayo

Hogarth

2014

Vaccine

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Tuberculosis (TB) remains one of the most important infectious diseases of man and animals, and the only available vaccine (BCG) requires urgent replacement or improvement. To facilitate this, the protective mechanisms induced by BCG require further understanding. As a live attenuated vaccine, persistence of BCG bacilli in the host may be a crucial mechanism. We have investigated the long term persistence of BCG following vaccination and the influence on the induced immune response and protection, using an established murine model. We sought to establish whether previously identified BCG-specific CD4 TEM cells represent genuine long-lived memory cells of a relatively high frequency, or are a consequence of continual priming by chronically persistent BCG vaccine bacilli. By clearing persistent bacilli, we have compared immune responses (spleen and lung CD4: cytokine producing T effector/TEM; TCR-specific) and BCG-induced protection, in the presence and absence of these persisting vaccine bacilli. Viable BCG bacilli persisted for at least 16 months post-vaccination, associated with specific CD4 T effector/TEM and tetramer-specific responses. Clearing these bacilli abrogated all BCG-specific CD4 T cells whilst only reducing protection by 1log10. BCG may induce two additive mechanisms of immunity: (i) dependant on the presence of viable bacilli and TEM; and (ii) independent of these factors. These data have crucial implications on the rational generation of replacement TB vaccines, and the interpretation of BCG induced immunity in animal models.

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Section: Discussionmentioning

confidence: 80%

Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis

Kaveh

García-Pelayo

Hogarth

2014

Vaccine

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“…We believe that in the absence of molecular signatures for the dynamic states of the infection that enable prediction of the course of disease and effects of interventions on correlates of protection, it may be necessary to think about developing a safe live infection challenge model that could be used in small-scale studies to measure ability to kill the pathogen (186). This has been a very important tool in studying protection in other infectious diseases, such as malaria and cholera.…”

Section: Discussionmentioning

confidence: 99%

TB or Not TB: That Is No Longer the Question

Modlin

Bloom

2013

Sci. Transl. Med.

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“…However, other studies (20)(21)(22) suggest that the main differences in BCG vaccination in different animal models are due to the substrain of BCG utilized, which leads to different qualitative and quantitative immune responses while resulting in similar reductions in the bacterial burden after challenge with an M. tuberculosis strain. Our study contradicts previous reports by Kramnik's laboratory which demonstrated similar adaptive T cell responses between congenic murine strains differing in the sst locus (15).…”

Section: Discussionmentioning

confidence: 99%

Differential Mycobacterium bovis BCG Vaccine-Derived Efficacy in C3Heb/FeJ and C3H/HeOuJ Mice Exposed to a Clinical Strain of Mycobacterium tuberculosis

Henao-Tamayo¹,

Obregón-Henao²,

Creissen³

et al. 2014

Clin. Vaccine Immunol.

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T he global epidemic of tuberculosis results in 8 million new tuberculosis cases per year, with an annual projected increase of 3% (1). It is estimated that between 5 and 10% of healthy individuals are susceptible to tuberculosis, and of these individuals, 85% develop pulmonary disease (2). At present, the only available vaccine against tuberculosis, Mycobacterium bovis bacillus Calmette-Guérin (BCG), has proven unreliable to fully protect against pulmonary tuberculosis in adults (3). Furthermore, a thorough immunological explanation for the variability in the efficacy of BCG is absent (4). Therefore, understanding the specific protective properties of BCG is vital for developing a more efficacious tuberculosis vaccine.The two small-animal models used most often for preclinical tuberculosis vaccine screening are the low-dose aerosol mouse and guinea pig models (5). Low-dose aerosol infection of guinea pigs with Mycobacterium tuberculosis produces a well-characterized disease that shares important morphological features with disease in humans, such as the development of necrotic granulomatous lesions (6). The majority of vaccine screening has been carried out with various mouse models due to their low cost and the wealth of immunological reagents, with the major drawback being the lack of tubercle necrosis formation.C3Heb/FeJ mice are capable of forming necrotic, hypoxic tubercle granulomas, while control C3H/HeOuJ mice form nonnecrotic granulomas (7-9). The hallmark of human tuberculosis is the development of a primary necrotic granuloma (7-9). The ability to be able to precisely characterize the protective immune response induced by vaccination during Mycobacterium tuberculosis infection in C3Heb/FeJ mice would greatly improve the usefulness of this animal model for the testing and evaluation of urgently needed new vaccines.In this study, we evaluated the impact of prior BCG vaccination on exposure of C3Heb/FeJ and C3H/HeOuJ mice to a low-dose aerosol of a W-Beijing strain of Mycobacterium tuberculosis. We evaluated the cellular influx and cytokine environment in mice made immune by prior BCG vaccination, in order to characterize how this might alter the composition of a protective immune response and granulomatous lesions in the lungs and spleens. Our results show that this is the first model system described to date that can be utilized to dissect differential vaccine-derived immune efficacy. MATERIALS AND METHODSMice. Specific-pathogen-free female C3Heb/FeJ and C3H/HeOuJ mice, 6 to 8 weeks old, were purchased from the Jackson Laboratories (Bar Harbor, ME). Mice were maintained in the biosafety level 3 facilities at Colorado State University and were given sterile water, chow, bedding, and enrichment for the duration of the experiments. The specific-pathogenfree nature of the mouse colonies was demonstrated by testing sentinel animals. All experimental protocols were approved by the Animal Care and Use Committee of Colorado State University.

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Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

Cited by 39 publications

References 41 publications

Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis

Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis

TB or Not TB: That Is No Longer the Question

Differential Mycobacterium bovis BCG Vaccine-Derived Efficacy in C3Heb/FeJ and C3H/HeOuJ Mice Exposed to a Clinical Strain of Mycobacterium tuberculosis

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