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New vaccines for tuberculosis are urgently needed to control this devastating disease.
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Several novel vaccine candidates have entered clinical trials.
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Candidates comprise subunit vaccines and whole-cell vaccines.
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Candidates target mostly prevention of disease; some also target prevention of infection.
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Some candidates target unexposed individuals, and others target exposed individuals.
Summary
Tuberculosis (TB) remains the deadliest infectious disease. The widely used bacille Calmette–Guérin (BCG) vaccine offers only limited protection against TB. New vaccine candidates for TB include subunit vaccines and inactivated whole-cell vaccines, as well as live mycobacterial vaccines. Current developments in TB vaccines are summarized in this review.
According to a recent analysis, tuberculosis (TB) has killed one billion people over the last 200 years, more victims than from smallpox, malaria, plague, influenza, cholera, and AIDS together.
Although TB is considered a disease of the past in some circles, it remains the deadliest contagious disease globally. In 2015, 10.4 million new cases of active TB were recorded, resulting in 1.8 million deaths (World Health Organization, WHO).
Approximately two billion people are infected with the causative agent, Mycobacterium tuberculosis, but only a small proportion of those individuals living with a latent TB infection (LTBI) are at risk of developing active disease (somewhere in the order of 10% over a lifetime).
Of the 15 million individuals suffering from co-infection with HIV and M. tuberculosis, 1.2 million have developed TB in 2015, rendering HIV co-infection a major driving force in the TB pandemic. An additional complication is the increasing incidence of multidrug-resistant (MDR)-TB annually; this accounts for half a million new cases with only a 50% chance of cure by drug treatment. Globally some 50 million individuals are already latently infected with MDR M. tuberculosis, creating a remarkable resource for future cases of active TB with insufficient treatment options.
This ambitious goal can only be accomplished successfully if more rapid diagnostics, new drugs for shorter therapy, and new vaccines to prevent pulmonary TB become available.
M. tuberculosis is transmitted by aerosol; if these bacteria reach the alveoli in the deeper lung, they are engulfed by alveolar macrophages and interstitial dendritic cells. These antigen-presenting cells transport M. tuberculosis to draining lymph nodes, where T lymphocytes are stimulated. Although antibodies are produced abundantly in response to M. tuberculosis infection, T-cells are generally considered the main mediators of protection during natural infection.
Such solid granulomas are present in the two billion individuals with LTBI. Active disease emerges when granulomas lose their sophisticated structure and become necrotic or even caseous due to massive cell death. During LTBI, M. tuberculosis reduces its metabolic and replicative activity to become dormant.
However, in caseous granulomas, M. tuberculosis reactivates its metabolism and replicates to reach high numbers. Rupture of a caseous granuloma allows for M. tuberculosis dissemination to other tissue sites and to the environment. Expectoration of cellular material containing M. tuberculosis serves as the source of disease transmission.
Although TB has long been considered to have two clearly defined states (LTBI and active TB disease), recent evidence suggests the existence of a whole spectrum of disease ranging from LTBI to active TB.
A vaccine against infant TB was introduced in 1921 by the French scientists Albert Calmette and Camille Guérin, which was accordingly named bacille Calmette–Guérin (BCG). This vaccine is now widely used to prevent severe forms of extrapulmonary TB such as miliary TB in infants.
The efficacy of bacillus Calmette–Guérin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature.
The efficacy of bacillus Calmette–Guérin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature.
BCG is an attenuated strain of Mycobacterium bovis, the etiological agent of TB in cattle. Although it is well tolerated, it can disseminate in immunocompromised individuals, notably HIV-infected persons, causing a disease termed BCGosis.
Accordingly, BCG is not recommended for HIV-exposed neonates in several countries.
Because of these limitations of BCG, novel TB vaccine candidates have been developed, of which several have reached the clinical trial pipeline. These TB vaccine candidates can be categorized into the following: (1) preventive pre-exposure vaccines, which are administered prior to first exposure to M. tuberculosis, typically to neonates; these are also known as priming vaccines; (2) preventive post-exposure vaccines, which are targeted at adolescents and adults with LTBI and prior BCG immunization; these are also known as boosting vaccines; (3) therapeutic vaccines, which are to be administered in adjunct with canonical TB drugs, notably to persons at higher risk of developing recurrent disease.
Figure 1 provides an overview of the major TB vaccine candidates in the clinical pipeline. Preventive vaccines come in three generic types: subunit vaccines, viable whole-cell vaccines, and inactivated whole-cell vaccines.
Figure 1Pipeline of major TB vaccines in clinical trials. RUTI and Vaccae are therapeutic vaccines; all other vaccines are preventive. For further explanations of antigens, adjuvants, and genetic modifications of the vaccines, see Table 1, Table 2, Table 3, Table 4, Table 5. (Abbreviations: GSK, Glaxo Smith Kline; MPIIB, Max Planck Institute for Infection Biology; VPM, Vakzine Projekt Management; SII, Serum Institute India; SSI, Statens Serum Institute; McMaster U, McMaster University; TBVI, Tuberculosis Vaccine Initiative; UOXF, University of Oxford; RIBSP, Research Institute for Biological Safety Problems.).
Subunit vaccines are composed of one or more antigens that are considered protective (Table 1). Often several antigens are combined to improve vaccine efficacy. Yet, protectivity is generally defined loosely and based on protection measured in one or more experimental animal models. To increase protectivity, antigens are either formulated with adjuvant or expressed by a recombinant viral vector (Table 2, Table 3). A number of current vectored vaccine candidates are based on recombinant adenovirus or vaccinia virus, many of which express the antigen 85A (Table 3).
The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: a randomized controlled trial.
A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults.
Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial.
Another viral vectored vaccine against TB harnesses a replication-deficient influenza virus expressing M. tuberculosis antigens. Some vectored vaccines are being developed not only as BCG boosters, but also as prime boost strategies comprising different viral vectors and/or M. tuberculosis antigen combinations.
The recombinant modified vaccinia Ankara (MVA) vector expressing antigen 85A (MVA85A) was one of the most advanced TB vaccines, but it failed to demonstrate protection in a preventive pre-exposure phase IIb trial.
Generally, these subunit vaccines are given as a boost after a BCG prime, with the aim of improving BCG-induced protection, i.e. to increase efficacy and prolong duration.
Table 1Antigens used in subunit TB vaccines
Vaccine
Antigen
Description
M72
Rv1196
PPE family member
Rv0125
Peptidase
H1
ESAT-6
Prominent antigen of Mtb encoded in region of difference 1
Since pre-exposure vaccines are mostly confronted with metabolically active M. tuberculosis, antigens for this type of vaccine are chosen from those expressed during the stages of active replication and metabolism. These include the hybrid H1 and H4 vaccines.
In contrast, post-exposure vaccines are administered to persons with M. tuberculosis in a dormant stage and need to include antigens expressed during latent infection. Ideally, a combination of antigens in the form of fusion proteins is administered to cover both active and latent stages. These so-called multistage vaccines include H56, M72, and ID93 (Table 1).
Viable vaccines were originally considered as replacement vaccines only and given instead of BCG. Hence, their first target population would be neonates (Table 4). The most advanced vaccine candidate is the recombinant BCG vaccine, VPM1002, which has shown a better safety and efficacy profile than standard BCG in preclinical models.
It has completed clinical phase I and phase II trials in adults and neonates and is currently being assessed in HIV-exposed neonates. It was shown that VPM1002 was well tolerated in adults with childhood BCG immunization, and protected against TB in an experimental post-exposure mouse model.
Hence, this vaccine is currently being developed also as a preventive post-exposure vaccine for adolescents and adults. Accordingly, a vaccination protocol has been submitted to prevent recurrence of TB in previously cured TB patients. Even after successful completion of drug treatment for active TB, over 10% of patients experience recurrence and develop TB for a second time, thus presenting a high risk group for vaccine trials. The second viable vaccine candidate that has successfully completed a phase I clinical trial is a double deletion mutant of M. tuberculosis termed MTBVAC.
Post-exposure vaccination with the vaccine candidate bacillus Calmette–Guérin Delta ureC::hly induces superior protection in a mouse model of subclinical tuberculosis.
3.1 Inactivated whole-cell mycobacterial vaccines for the prevention of TB
Inactivated whole-cell mycobacterial vaccines used in a multiple-dose schedule were shown to be effective preventive vaccines in experimental models and in humans over 70 years ago, but were not developed further after single-dose BCG became the de facto preventive vaccine of choice.
More recently SRL172, an inactivated whole-cell vaccine derived from a non-tuberculous Mycobacterium, was shown to be safe, well-tolerated, and immunogenic in phase I and II trials. Efficacy was subsequently documented in a phase III randomized, controlled, booster trial among HIV-infected adults in Tanzania,
DarDar Study Group. Prevention of tuberculosis in bacille Calmette–Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine.
making it the only new TB vaccine in development for which efficacy in humans has been demonstrated. The SRL172 master cell bank was used to develop scalable manufacturing for the booster vaccine now known as DAR-901. Safety and tolerability were demonstrated in a phase I trial of the DAR-901 booster in adults primed with BCG in childhood. DAR-901 induced both cellular and humoral responses to mycobacterial antigens comparable to those observed with SRL172, but did not result in conversion of the interferon gamma release assay (IGRA). A randomized, controlled phase IIb trial is now underway for the prevention of infection with M. tuberculosis among adolescents in Tanzania.
A heat-inactivated whole-cell vaccine derived from Mycobacterium vaccae (‘Vaccae’) is also being studied for the prevention of TB after already being approved in China for the adjunctive treatment of TB.
The prevention trial was initiated in 2013 and was designed to enroll 10 000 subjects with a positive tuberculin skin test, but additional public information is not presently available (Table 5).
Since it is not known what antigens will induce protective immunity in humans, these polyantigenic vaccines have a greater likelihood than subunit vaccines of including the critical epitopes required for protective efficacy.
3.2 Vaccines for the treatment of TB
Several vaccines are being developed to improve treatment outcomes in active TB (reduce mortality or relapse rates). This is a particular challenge in MDR-TB and extensively drug-resistant (XDR)-TB with extremely low cure rates of less than 50%, providing a greater opportunity for identifying the therapeutic efficacy of an investigational vaccine. The biological hypothesis is that additional stimulation with mycobacterial antigens may further enhance the immune response and improve bacterial killing. However, there are experimental data suggesting that certain types of excessive immune response might be detrimental in the immune control of TB in humans.
CD4 T cell-derived IFN-gamma plays a minimal role in control of pulmonary Mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease.
Addition of Mycobacterium indicus pranii (MIP) vaccine as an immunotherapeutic with standard chemotherapy in borderline leprosy: a double blind study to assess clinical improvement (A preliminary report).
(Table 5). A phase II study of Mw as an adjunct to therapy for TB has been completed and is being analyzed. A preclinical study of Mw administration by the aerosol route will examine immune responses in guinea pig and mouse models.
RUTI is a vaccine being developed to improve the outcomes in the treatment of both LTBI and TB disease and to reduce exposure to antibiotics (Table 5). Its mechanism of action is based on the induction of a polyantigenic cellular response to non-replicating bacilli contained in detoxified cell wall nano-fragments of M. tuberculosis. A phase I trial demonstrated safety and immunogenicity and a phase II trial showed safety and immunogenicity in both HIV-negative and HIV-positive volunteers with LTBI.
Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection.
A phase IIa trial is planned to investigate the safety and immunogenicity of RUTI therapeutic immunization in patients with MDR-TB.
4. Concluding remarks
Until recently the development of new vaccines against TB was directed towards containing M. tuberculosis by prolonging LTBI and blocking active TB disease.
Although an effective vaccine to prevent TB disease would be an applaudable achievement, the sterile elimination or prevention of M. tuberculosis infection would ultimately be preferred. Although the biological mechanisms that might lead to sterile M. tuberculosis elimination or the prevention of M. tuberculosis infection are not known, recent evidence suggests that BCG immunization is capable of preventing infection at least in part.
Effect of BCG vaccination on risk of Mycobacterium tuberculosis infection in children with household tuberculosis contact: a prospective community-based study.
Vaccine Prevention of Sustained Mycobacterium tuberculosis Infection Summary Group
Developing vaccines to prevent sustained infection with Mycobacterium tuberculosis: Conference proceedings: National Institute of Allergy and Infectious Diseases, Rockville, Maryland USA, November 7, 2014.
These prevention of infection trials employ IGRAs, which are based on a simple blood test to detect infection.
Because TB is a poverty-related disease, cost matters. Hence, it is critical to accelerate clinical trials and at the same time reduce their cost. One option towards this goal is stratification based on high-risk groups.
These include miners, who are at a markedly elevated risk of developing TB, and patients with successfully treated TB who have a high rate of recurrent TB, as described above. Alternatively, biomarkers that predict progression towards active TB would allow the stratification of study participants at greatest risk of developing active TB disease within the duration of a standard clinical trial.
Indeed, biosignatures that can predict progression to active TB are currently being developed. These signatures comprise changes in the gene expression of defined markers at high sensitivity so that they most likely diagnose subclinical incipient TB.
Even though the development of an improved vaccine against TB presents major challenges on several fronts, it is a goal worth pursuing. After all, an effective vaccine that prevents pulmonary TB could make a major contribution to the goal of reducing TB morbidity and mortality by 90% and 95%, respectively, by the year 2035.
Acknowledgements
The authors thank Souraya Sibaei for excellent secretarial assistance and Diane Schad for graphics work.
Funding: SHEK acknowledges support from The European Union's Seventh Framework Programme (EU FP7) ADITEC (HEALTH-F4-2011-280873); the EU Horizon 2020 project TBVAC 2020 (grant number 643381); The Bill & Melinda Gates Foundation (BMGF) GC6-2013, #OPP 1055806 and #OPP 1065330; the Bundesministerium für Bildung und Forschung (BMBF) project “Infect Control 2020”. FvR acknowledges support from the Global Health Innovative Technology Fund (GHIT, grant number G2015-147) and the US National Institutes of Health (Fogarty International Center D43-TW006807).
Conflict of interest: SHEK is co-inventor of the TB vaccine VPM1002. CFvR is the sponsor for DAR-901.
The efficacy of bacillus Calmette–Guérin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature.
The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: a randomized controlled trial.
A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults.
Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial.
Post-exposure vaccination with the vaccine candidate bacillus Calmette–Guérin Delta ureC::hly induces superior protection in a mouse model of subclinical tuberculosis.
DarDar Study Group. Prevention of tuberculosis in bacille Calmette–Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine.
CD4 T cell-derived IFN-gamma plays a minimal role in control of pulmonary Mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease.
Addition of Mycobacterium indicus pranii (MIP) vaccine as an immunotherapeutic with standard chemotherapy in borderline leprosy: a double blind study to assess clinical improvement (A preliminary report).
Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection.
Effect of BCG vaccination on risk of Mycobacterium tuberculosis infection in children with household tuberculosis contact: a prospective community-based study.
Vaccine Prevention of Sustained Mycobacterium tuberculosis Infection Summary Group
Developing vaccines to prevent sustained infection with Mycobacterium tuberculosis: Conference proceedings: National Institute of Allergy and Infectious Diseases, Rockville, Maryland USA, November 7, 2014.
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