TB vaccines; promoting rapid and durable protection in the lung
Introduction
Tuberculosis (TB) kills about 1.5 million people each year and although novel diagnostic methods and intense treatment schemes like DOTS (directly observed therapy short course) have been widely implemented in high prevalence areas, worldwide mortality has not been reduced at the expected or desired rates [1].
Adding to the magnitude and complexity of the TB problem, mortality represents only the tip of the iceberg, as more than two billion people worldwide are clinically healthy but latently infected with Mycobacterium tuberculosis (Mtb). Latent TB infection (LTBI) provides an infinite source of potential reactivation disease and transmission. These numbers make TB the most widespread infectious agent and together with HIV the top cause of death from infectious diseases [1]. The HIV epidemic is the driving force of the TB epidemic in many countries and results in an increasing number of cases involving MDR-TB, XDR-TB and TDR (Multi-Drug Resistant, eXtensively-Drug Resistant, and Total-Drug Resistant) TB [1].
The Bacillus Calmette–Guérin (BCG) vaccine was developed a century ago and is used extensively in most parts of the world with the exception of Western Europe and North America. This vaccine has some protective effect in children but fails to protect against pulmonary tuberculosis in adults. Mtb and humans have co-evolved since the most early human origin [2], and this has allowed the pathogen to adapt and develop a refined set of countermeasures that represent a very difficult target for the immune system.
The result is a pathogen that is rarely cleared by the natural immune response but instead establishes a long-term chronic infection [3]. Attempts to identify adaptive immune responses that are missing or are insufficiently expressed in individuals that develop disease has so far not been successful [4, 5]. However, although clearly insufficient for the control of TB in individuals that develop disease the immune response raised during the natural infection still guides most attempts to develop vaccines.
Section snippets
Vaccine strategies against TB
In the last 10 years, there has been substantial progress in the TB vaccine field, with more than a dozen novel vaccines in clinical trials. These vaccines can be divided into different categories depending on the time point of administration compared to the infection and/or prior BCG vaccination and the delivery system used (see Figure 1 for a schematic representation and description of the vaccines in clinical trials). Live mycobacterial vaccines such as recombinant BCG or attenuated Mtb are
TB: infection, immunity and antigens
Mtb is an airborne pathogen that can establish infection in susceptible individuals when aerosolized water droplets, even those containing very few infectious bacteria, are inhaled. The bacteria are thought to first be taken up by alveolar macrophages and are later acquired by other myeloid cells, including neutrophils and dendritic cells [10]. Importantly, virulent mycobacteria utilize cell surface lipids to restrict TLR-driven recruitment of host-protective immune cells to the initial site of
Protective immunity and memory
The goal of all TB vaccines currently in clinical trials is to induce memory T cells capable of mounting a protective response to subsequent Mtb challenge. Animal models suggest that this protective T cell response should have two principal components. First, it should be rapid and robust at the primary site of infection in the lung, and second, it should be durable [17]. Achieving both of these goals through vaccination requires careful consideration of the functional properties of distinct
Conclusions
Discovery of new and improved TB vaccines has been complicated and delayed by major gaps in our understanding of how immunity to TB manifests itself at the site of infection in the lung. Without this knowledge, too many efforts in TB vaccine discovery have been dominated by trial and error with the only conclusive read-out being the ability to protect against challenge in experimental animal models. Given that there is no direct correlation between protection and the level of systemic IFNγ
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Karen Korsholm and Christina Gry Paulsen for help preparing the figures and Joshua Woodworth for critically reading the manuscript.
Peter Andersen is supported by the European Union's Seventh Framework Programme (EU FP7) ADITEC (HEALTH-F4-2011-280873), the European Union's Research and Innovation Programme Horizon 2020 (EU H2020) TBVAC2020 (H2020-PHC-2014-2015/H2020-PHC-2014, Grant # 643381), the Innovative Medicines Initiative (IMI) Joint Undertaking ‘Biomarkers for Enhanced Vaccine
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Cited by (31)
Immunological and physical evaluation of the multistage tuberculosis subunit vaccine candidate H56/CAF01 formulated as a spray-dried powder
2018, VaccineCitation Excerpt :Spray drying provides the opportunity for particle engineering of respirable vaccine powders with aerodynamic properties suitable for deposition at the lung mucosa upon inhalation [18,19]. This might prove beneficial because initial infection with Mtb takes place in the deep lungs, followed by formation of granulomas adjoining bronchial surfaces and alveoli: Aerosol delivery of a dry powder-based TB vaccine directly into the deep lungs might therefore offer immunological advantage by virtue of inducing both mucosal and systemic immune responses [20–22]. The applicability of dry powder vaccine formulations for inhalation has previously been demonstrated for vaccination against influenza and measles viruses [23,24].
Safety and immunogenicity of the novel tuberculosis vaccine ID93 + GLA-SE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial
2018, The Lancet Respiratory MedicineCitation Excerpt :We proposed that a vaccine should ideally induce immune responses against a range of these antigens, irrespective of the infection stage. The phenotype, functional capacity, and tissue location of antigen-specific T cells are also likely to be crucial in preventing disease.10 Additionally, recent findings suggest that antibodies might contribute to infection outcome, including protection against disease.11
Pharmacokinetic studies of a three-component complex that repurposes the front line antibiotic isoniazid against Mycobacterium tuberculosis
2017, TuberculosisCitation Excerpt :The Bacillus Calmette-Guérin (BCG) vaccine has been available for almost ninety years, but its inconsistent performance has resulted in the disease persisting in many populations [8]. New vaccines have advanced through various levels of pre-clinical, animal, and human trials, but none have been deployed worldwide [9,10]. The small molecule antibiotic Bedaquiline was the first new drug approved for tuberculosis in over forty years when it was introduced in 2012 [11,12].
Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis
2017, Cell Host and MicrobeCitation Excerpt :The challenge of devising a T cell-targeted vaccine against Mtb is heightened by the recent understanding that antigen-specific memory CD4 T cells that are less differentiated exert greater control of murine Mtb infection than highly differentiated effector cells (Lindenstrøm et al., 2013; Moguche et al., 2015; Sakai et al., 2014a; Torrado et al., 2015; Vogelzang et al., 2014). The protective capacity of these “less differentiated” CD4 T cells reflects their superior ability to proliferate, maintain their cytokine-producing capacity, and home to infected tissues (Andersen and Urdahl, 2015; Sakai et al., 2014b; Woodworth et al., 2017). Thus, while choosing persistently expressed vaccine antigens is likely to be important, these same antigens may drive T cells toward terminal differentiation and dysfunction.
Antibodies and tuberculosis
2016, TuberculosisCitation Excerpt :Despite demonstrating protection in some animal models, and inducing antigen specific CD4+ T-cells, MVA85A was unable to add to the protection assumed to be provided by BCG [7,8]. Many candidate vaccines against TB target a similarly narrow immune repertoire, and thus the disappointing outcome of the MVA85A trials has provided impetus to explore a wider range of immune responses in protection against TB [9,10]. Antibody-mediated immunity (AMI) is one such approach.