Elsevier

Current Opinion in Immunology

Volume 35, August 2015, Pages 55-62
Current Opinion in Immunology

TB vaccines; promoting rapid and durable protection in the lung

https://doi.org/10.1016/j.coi.2015.06.001Get rights and content

Highlights

  • Most TB vaccine candidates aim to amplify IFN-γ producing memory T cells in the blood.

  • The frequency of IFN-γ producing T cells in blood does not correlate with protection.

  • Animal models suggest vaccine-induced T cell responses should be rapid and sustained.

  • Lung resident-memory T cells may prevent or curb early infection.

  • Central memory T cells migrate to the site of infection and provide durable protection.

TB vaccine discovery has focused on IFN-γ both for the selection of antigens and vaccine delivery strategies. Recent breakthroughs in our understanding of the requirements for immunological memory and the expression of immunity to TB in the lung now provide a framework for reconsidering that strategy. We will discuss the status of the TB vaccine field, recent insights into the role of central memory cells and the potential of tissue-resident memory cells in vaccine promoted protection against TB.

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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