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Moving tuberculosis vaccines from theory to practice

Abstract

Tuberculosis (TB) vaccine research has reached a unique point in time. Breakthrough findings in both the basic immunology of Mycobacterium tuberculosis infection and the clinical development of TB vaccines suggest, for the first time since the discovery of the Mycobacterium bovis bacillus Calmette–Guérin (BCG) vaccine more than a century ago, that a novel, efficacious TB vaccine is imminent. Here, we review recent data in the light of our current understanding of the immunology of TB infection and discuss the identification of biomarkers for vaccine efficacy and the next steps in the quest for an efficacious vaccine that can control the global TB epidemic.

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Acknowledgements

The authors thank P. Højlund for expert secretarial assistance, K. Korsholm for the graphical layout and R. Mortensen and J. Woodworth for valuable discussions and input on the content of the paper.

Reviewer information

Nature Reviews Immunology thanks P.-J. Cardona and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

The authors contributed equally to all aspects of the article.

Competing interests

T.J.S. declares no competing interests. P.A. is a named co-inventor on patents covering the H56:IC31 tuberculosis vaccine. The patents are assigned to the Statens Serum Institute, a not for profit organization under the Danish Ministry of Health.

Correspondence to Peter Andersen or Thomas J. Scriba.

Glossary

Incipient TB

A state of Mycobacterium tuberculosis infection in which the host is likely to progress to active tuberculosis (TB) disease but has not yet manifested clinical symptoms, radiographic abnormalities or microbiological evidence of active disease. Can be detected using transcriptomic or proteomic biomarkers of inflammation.

Subclinical TB

A state of Mycobacterium tuberculosis infection in which the host has radiographic abnormalities or microbiological evidence of active tuberculosis (TB) disease but has not yet manifested clinical symptoms of active disease.

Priming vaccines

Vaccines that mediate sensitization or stimulation of an immune response with antigen for the first time; that is, the vaccines prime the immune response.

Booster vaccines

Vaccines that are typically given after an earlier priming vaccine and further stimulate an immune response that already exists to an antigen to increase the response magnitude or modulate the function of the response; that is, the vaccines boost the pre-existing immune response.

Correlates of protection

(COP). A measurable feature, often a functional characteristic of an immune response, that associates with protection against becoming infected and/or developing disease.

ELISpot assay

(Enzyme-linked immunosorbent spot assay). A type of immune assay that quantifies the frequency of protein-secreting single cells on the basis of enzyme-linked detection of protein spots on immune-absorbent membranes.

Inducible bronchus-associated lymphoid tissue

A tertiary lymphoid structure that consists of lymphoid follicles in the lungs or bronchus and that is a site for priming immune responses.

Reactivation TB

Also known as post-primary tuberculosis (TB) or secondary TB; TB that typically occurs months to years after the initial infection and is associated with distinct disease manifestation compared to primary TB. Reactivation frequently occurs in the setting of weakened immunity and usually involves the lung apex.

Cavitation

The formation of a cavity in the centre of a tuberculosis (TB) nodule or area of consolidation, usually in the upper lung or apex. Cavities may be detected by chest radiography or computed tomography and are a characteristic feature of post-primary or adult type TB.

Chemotherapy for active TB

Drug-sensitive tuberculosis (TB) disease is typically treated with a 4-drug regimen of rifampicin, isoniazid, pyrazinamide and ethambutol for 2 months (the intensive phase of treatment), followed by isoniazid and rifampicin for 4 months (the continuation phase).

IFNγ release assay

(IGRA). A test for infection with Mycobacterium tuberculosis (Mtb) that measures IFNγ release by T cells after stimulation of blood or peripheral blood mononuclear cells with Mtb-specific peptides. IGRA conversion is an efficacy outcome in clinical trials that test prevention of Mtb infection, defined as conversion to a positive test without reversion to negative status in the next 2 consecutive IGRA tests, 3 months apart (that is, 3 consecutive positive IGRA results).

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Fig. 1: The balance between Mtb-specific T cell differentiation into either T effector memory or T central memory cells.
Fig. 2: The effects of immunological sensitization to mycobacteria on vaccine efficacy.