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Mycobacterium tuberculosis sigE mutant ST28 used as a vaccine induces protective immunity in the guinea pig model.

ABSTRACT: With more than 9 million new infections and 1.5 million deaths claimed every year, tuberculosis remains one of the major scourges of humankind. The only vaccine available against this disease, the attenuated strain Mycobacterium bovis, BCG is effective against severe forms of the disease in infants, but scarcely effective in protecting adults from the pulmonary form of the disease, thus not stopping transmission. Consequently, the development of an effective anti-tuberculosis vaccine is a major goal for improving global health. The most common concept is that a more effective vaccine should include a first immunization with a live vaccine followed by the administration of an acellular boosting vaccine. In this approach, the live vaccine might be either BCG or a different, more efficient attenuated strain. Recently, we showed that a Mycobacterium tuberculosis mutant missing the gene encoding for the extracellular function sigma factor SigE, is strongly attenuated and is able to induce a more effective protection from M. tuberculosis infection compared to BCG in mice. We now further characterize the protective potential of this novel strain in the guinea pig model of tuberculosis. In the guinea pig, it had limited growth but induced a Th1 immune response and was able to significantly reduce the number of colony forming units as well as prolong survival. Taken together these data provide evidence for the use of the M. tuberculosis sigE mutant as the basis for further development as a vaccine against infection.

SUBMITTER: Troudt J

PROVIDER: S-EPMC5570617 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Mycobacterium tuberculosis sigE mutant ST28 used as a vaccine induces protective immunity in the guinea pig model.

Troudt JoLynn J Creissen Elizabeth E Izzo Linda L Bielefeldt-Ohmann Helle H Casonato Stefano S Manganelli Riccardo R Izzo Angelo A AA

Tuberculosis (Edinburgh, Scotland) 20170724

With more than 9 million new infections and 1.5 million deaths claimed every year, tuberculosis remains one of the major scourges of humankind. The only vaccine available against this disease, the attenuated strain Mycobacterium bovis, BCG is effective against severe forms of the disease in infants, but scarcely effective in protecting adults from the pulmonary form of the disease, thus not stopping transmission. Consequently, the development of an effective anti-tuberculosis vaccine is a major ...[more]

PMID: 28802412

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Project description:BACKGROUND:The current BCG vaccine induces only short-term protection against Mycobacterium tuberculosis (Mtb), suggesting its failure to generate long-lasting memory T cells. Previously, we have demonstrated that a self-adjuvanting peptide of Mtb (L91), successfully generated enduring memory Th1 cells. Consequently, we investigated if L91 was able to recuperate BCG potency in perpetuating the generation of memory T cells and protection against Mtb infected mice. METHODS:In the present study, we evaluated the potency of a self adjuvanting Mtb peptide vaccine L91 in invigorating BCG immune response against Mtb in mice. Female BALB/c mice were immunized with BCG. Later, they were boosted twice with L91 or an antigenically irrelevant lipidated influenza virus hemagglutinin peptide (LH). Further, PBMCs obtained from BCG vaccinated healthy subjects were cultured in vitro with L91. T cell responses were determined by surface markers and intracellular cytokine staining. Secretion of cytokines was estimated in the culture supernatants (SNs) by ELISA. RESULTS:Compared to the BCG-vaccinated controls, L91 booster significantly enhanced the percentage of memory Th1 cells and Th17 cells and reduced the mycobacterial burden in BCG primed and L91-boosted (BCG-L91) group, even after 229 days of BCG vaccination. Further, substantial augmentation in the central (CD44hiCD62LhiCD127hi) and effector memory (CD44hiCD62LloCD127lo) CD4 T cells was detected. Furthermore, greater frequency of polyfunctional Th1 cells (IFN-γ+TNF-α+) and Th17 cells (IFN-γ+IL-17A+) was observed. Importantly, BCG-L91 successfully prevented CD4 T cells from exhaustion by decreasing the expression of PD-1 and Tim-3. Additionally, augmentation in the frequency of Th1 cells, Th17 cells and memory CD4 T cells was observed in the PBMCs of the BCG-vaccinated healthy individuals following in vitro stimulation with L91. CONCLUSIONS:Our study demonstrated that L91 robustly reinvigorate BCG potency to invoke enduring protection against Mtb. This novel vaccination stratagem involving BCG-priming followed by L91-boosting can be a future prophylactic measure to control TB.

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Mycobacterium tuberculosis sigE mutant ST28 used as a vaccine induces protective immunity in the guinea pig model.

Publications

Mycobacterium tuberculosis sigE mutant ST28 used as a vaccine induces protective immunity in the guinea pig model.

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