Review
Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review

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Summary

Tuberculosis continues to kill 1·4 million people annually. During the past 5 years, an alarming increase in the number of patients with multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has been noted, particularly in eastern Europe, Asia, and southern Africa. Treatment outcomes with available treatment regimens for drug-resistant tuberculosis are poor. Although substantial progress in drug development for tuberculosis has been made, scientific progress towards development of interventions for prevention and improvement of drug treatment outcomes have lagged behind. Innovative interventions are therefore needed to combat the growing pandemic of multidrug-resistant and extensively drug-resistant tuberculosis. Novel adjunct treatments are needed to accomplish improved cure rates for multidrug-resistant and extensively drug-resistant tuberculosis. A novel, safe, widely applicable, and more effective vaccine against tuberculosis is also desperately sought to achieve disease control. The quest to develop a universally protective vaccine for tuberculosis continues. So far, research and development of tuberculosis vaccines has resulted in almost 20 candidates at different stages of the clinical trial pipeline. Host-directed therapies are now being developed to refocus the anti-Mycobacterium tuberculosis-directed immune responses towards the host; a strategy that could be especially beneficial for patients with multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis. As we are running short of canonical tuberculosis drugs, more attention should be given to host-directed preventive and therapeutic intervention measures.

Introduction

At present, the development of new drugs for the treatment of tuberculosis does not keep pace with the development of Mycobacterium tuberculosis drug resistance. Evidently, innovative interventions are needed to combat the emerging pandemic of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. At present, research and development of tuberculosis vaccines is financed via global financial investments in the order of US$100 million per year.1 Investment in preclinical research and development has yielded almost 20 vaccine candidates for tuberculosis—most of which still remain at different stages of the clinical trial pipeline with few dropouts. Moreover, several new candidates are ready to enter the pipeline soon. The development of most vaccine candidates is jointly sponsored by the public sector with the aim to advance the research and development of tuberculosis vaccines, with substantial contributions from private companies.

The BCG vaccine, which is extensively used as part of the Expanded Program on Immunisation, prevents against only severe forms of childhood tuberculosis, and does not protect against the most prevalent form of this disease, pulmonary tuberculosis, in all age groups.2 Thus, an improved vaccine against tuberculosis is desperately needed. Preclinical research and development can benefit from research in related specialties—notably, with regards to the development of novel adjuvants and vectors. New vaccine candidates are being created in other specialties with new vectors such as simian adenovirus, cytomegalovirus, and lymphocytic choriomeningitis virus.3 Although research and development for a universally protective tuberculosis vaccine continues, novel host-directed therapies might be helpful to augment biologically relevant host immune responses; a strategy that could be particularly beneficial for patients with multidrug-resistant and extensively drug-resistant tuberculosis. This Review discusses advances and progress being made in host-directed interventions, including the clinical trial pipeline for new tuberculosis vaccines and therapeutic concepts targeting host defense mechanisms to improve treatment outcomes.

Key messages

  • Tuberculosis continues to kill 1·4 million people annually, and numbers of patients with drug-resistant tuberculosis have increased alarmingly

  • A novel, safe, widely applicable and more effective vaccine against tuberculosis is needed for disease control

  • Vaccine research and development for tuberculosis has brought forward almost 20 vaccine candidates, many of which are at different stages of the clinical trial pipeline

  • Vaccines for tuberculosis can be classified according to their target population; therapeutic or preventive vaccines; composition (ie, killed mycobacteria, viable recombinant mycobacteria, viral-vectored and adjuvanted subunit vaccines); time of administration (pre-exposure and postexposure vaccines), and according to BCG (ie, replacement and heterologous prime-boost vaccines)

  • Host-directed therapies aim to eliminate Mycobacterium tuberculosis in the host—eg, by augmenting focused, clinically effective anti-M tuberculosis-directed immune responses, or by limiting non-productive, tissue-damaging inflammation in tuberculosis, a strategy that could be particularly beneficial for patients with drug-resistant tuberculosis

  • Host-directed therapies contain different groups of compounds, including cytokines and so-called repurposed drugs, that target biologically and clinically relevant checkpoints in anti-M tuberculosis-directed host response pathways

Section snippets

Immune orchestration against M tuberculosis

Tuberculosis is primarily a pulmonary disease; the respiratory tract serves as port of entry and the lung as the prime organ of disease manifestation.4, 5 At the site of M tuberculosis infection, granulomas are formed. Protection against and pathogenesis of tuberculosis are cell mediated,6, 7 primarily comprising T lymphocytes and mononuclear phagocytes focused on granulomas (figure 1). Granulomas are composed of different T-lymphocyte subsets and different myeloid cell types, which, within the

Host-directed therapies

At first glance, vaccination and therapy seem to be two unrelated topics. About 120 years ago, Robert Koch25 attempted to combine both themes by vaccinating patients with tuberculosis with tuberculin; his efforts, however, were met with failure. Tuberculosis vaccines aim to induce long-lasting immune responses that would eliminate or effectively contain M tuberculosis upon encounter. These (adaptive) immune responses are thought to be proinflammatory and Th1 T cell oriented. M tuberculosis

Autophagy and host-directed therapies

Autophagy is the physiological response to stimuli that activate autophagy and related genes (ATG), and is a catabolic pathway that leads to destruction of cellular components via lysosomal compartments.102 Autophagy is relevant to treatment because conventional antituberculosis drugs work, partly, via regulation of autophagy; autophagy plays a part in BCG vaccination; and candidate repurposed drugs for antituberculosis treatment might work via modulation of host autophagy.

The physiological

Host-directed pathways: controlling immunopathology and favouring M tuberculosis clearance

Establishment of fine-tuned immune responses plays a key part in improvement of clinical outcomes of tuberculosis. Additionally, the increasing need for new chemotherapeutic interventions has encouraged investiture of much effort into repurposing clinically approved drugs targeting biological pathways involved in the host defence against M tuberculosis. This section discusses pharmacological and biological interventions of immunologically relevant indications that might contribute to effective

Biological interventions with recombinant cytokines

Adjunctive therapy with a range of proinflammatory human cytokines has been explored to augment the Th1 immune response in human beings with tuberculosis, particularly in patients with advanced stages of disease or multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis. Because of the small number of patients treated with cytokine therapies and the paucity of placebo-controlled randomised clinical trials, the full potential of cytokine therapies for the treatment of

Biological intervention with vitamin D

Vitamin D (1,25-dihydroxyvitamin D) deficiency has been associated with increased risk of tuberculosis.171 The exact mechanisms have not been determined, but vitamin D seems to effect the gene transcription of antimicrobial peptides DEFB4/HBD2 and cathelicidin.172 New studies suggest that vitamin D induces interleukin 1β, which leads to reduction of the burden of M tuberculosis, via interaction of the NLRP3/caspase 1 inflammasome in infected cells.51 Vitamin D therapy can therefore be deemed a

Vaccine candidates in clinical trials

Vaccine candidates can be segregated into different groups based on the following criteria: 1) according to their target population, either therapeutic or preventive vaccines; 2) according to their composition, preparations of killed mycobacteria, viable recombinant mycobacteria, or viral-vectored and adjuvanted subunit vaccines; 3) according to time of administration with regards to natural infection with M tuberculosis, pre-exposure or postexposure vaccines; and 4) according to their relation

The tuberculosis vaccine trial pipeline

Phase 1 trials for vaccine candidates of tuberculosis are mainly done in adults; first in the geographical area of development, and second in a developing country with a high prevalence of tuberculosis. The primary goal of these trials is safety assessment and, generally, first insights into the immunogenicity of these candidates are included. Frequently, clinical trials comprise both tuberculin skin test (TST)+ and TST individuals, that is, individuals who have had previous BCG vaccination or

Future outlook

In the natural course of tuberculosis in most human beings, M tuberculosis can be eradicated by way of innate immune mechanisms.213 However, our understanding of the complexity of human immune defence against M tuberculosis is at present too restricted to augment the immune response in the right direction for most patients who are not naturally cured of the disease to enable control of the growth of M tuberculosis and subsequent clearance of infection in the absence of drug treatment. Recent

Search strategy and selection criteria

We searched publications in the English language in PubMed and Google Scholar (1940–2013), the Cochrane Library (2001–12), and Embase (2001–12) with the terms “tuberculosis”, “Mycobacterium tuberculosis”, and “TB”, combined with “vaccines', “new vaccines”, “vaccination”, “immunization”, “vaccine safety”, “subunit vaccines”, “biomarkers”, “vaccine development”, “vaccine trials”, and the terms “host-directed therapy” combined with “TB”, “tuberculosis”, “Mycobacterium tuberculosis'', “adjunct

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