Abstract
Tuberculosis (TB) remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, Bacillus Calmette–Guérin, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mycobacterium tuberculosis (Mtb) in infected macrophages and dendritic cells that support disease progression and block development of protective immunity. This review provides an assessment of the known immunoregulatory mechanisms altered by Mtb, and how new interventions may reverse these effects. Examples include blocking of inhibitory immune cell coreceptor checkpoints (e.g., programed death-1). Conversely, immune mechanisms that strengthen immune cell effector functions may be enhanced by interventions, including stimulatory immune cell coreceptors (e.g., OX40). Modification of the activity of key cell “immunometabolism” signaling pathway molecules, including mechanistic target of rapamycin, glycogen synthase kinase-3β, wnt/β-catenin, adenosine monophosophate-activated protein kinase, and sirtuins, related epigenetic changes, and preventing induction of immune regulatory cells (e.g., regulatory T cells, myeloid-derived suppressor cells) are powerful new approaches to improve vaccine responses. Interventions to favorably modulate these components have been studied primarily in oncology to induce efficient antitumor immune responses, often by potentiation of cancer vaccines. These agents include antibodies and a rapidly increasing number of small molecule drug classes that have contributed to the dramatic immune-based advances in treatment of cancer and other diseases. Because immune responses to malignancies and to Mtb share many similar mechanisms, studies to improve TB vaccine responses using interventions based on “immuno-oncology” are needed to guide possible repurposing. Understanding the regulation of immune cell functions appropriated by Mtb to promote the imbalance between protective and pathogenic immune responses may guide the development of innovative drug-based adjunct approaches to substantially enhance the clinical efficacy of TB vaccines.
Highlights
Tuberculosis (TB) caused by the bacillus Mycobacterium tubercu losis (Mtb), is the most common infectious cause of death worldwide
The lack of known correlates of protection associated with different stages of TB infection and disease has been a barrier to the clinical evaluation of vaccine candidates, and the TB vaccine field is redirecting its attention to basic discovery and preclinical development [17]
As inhaled drug and vaccine delivery platforms gain recognition and prolonged use of autophagy inducers can result in immunosuppression, rapamycin delivered in poly lactide-c o-glycolide nano particles can maintain high localized intracellular drug concentration and minimize systemic side effects [40, 44]
Summary
Tuberculosis (TB) caused by the bacillus Mycobacterium tubercu losis (Mtb), is the most common infectious cause of death worldwide. The lack of known correlates of protection associated with different stages of TB infection and disease has been a barrier to the clinical evaluation of vaccine candidates, and the TB vaccine field is redirecting its attention to basic discovery and preclinical development [17]. New strategies are needed to improve vaccine efficacy based on both a better understanding of the mechanisms mediating protective immunity and mechanism of subversion of host immune responses by immunopathogenic components of Mtb. Opinion on the balance between protective and destructive responses to Mtb infection in humans and animal models and the functional role of granuloma is still evolving [18, 19]. A better understanding of the features that contribute to protective host responses to Mtb infection will aid in the identification of drugs that can be repurposed for use to potentiate current TB vaccination strategies. This review will focus on the potential of these interventions to be tested as adjunct strategies to shift the balance of TB vaccines toward protective responses and potentiate host responses induced by vaccines
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