Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination

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.

Mucosal-associated invariant and γδ T cell subsets respond to initial Mycobacterium tuberculosis infection

“…Tuberculosis (TB) remains a leading cause of global mortality from an infection (1). Understanding the innate immune mechanisms of clearance of primary Mycobacterium tuberculosis (Mtb) infection and control of latent infection are critical to definitive control over the epidemic (2) and may inform TB vaccine design and immunotherapy (3,4). Host immune responses during Mtb infection involve a complex and incompletely understood immunoregulatory network that includes both innate and adaptive arms of the immune system (5,6).…”

Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model

“…There has been considerable recent interest in the use of adjunctive host-directed therapy to enhance activity of anti-tuberculosis drugs 1 , 2 . Drugs that inhibit cyclo-oxygenase (COX) enzymes have been identified as a class of potential value in tuberculosis (TB), with a number of actions that may be of putative benefit.…”

Janus-Faced Myeloid-Derived Suppressor Cell Exosomes for the Good and the Bad in Cancer and Autoimmune Disease

“…IL10 promotes TH2 deviation and type 2 macrophage (Mϕ) polarization. Finally, ADAM17 leads to CD62L cleavage, which prohibits T cell homing ( 42 , 43 ).…”