Strategies to Improve Vaccine Efficacy against Tuberculosis by Targeting Innate Immunity

Abstract

The global tuberculosis epidemic is the most common cause of death after infectious disease worldwide. Increasing numbers of infections with multi- and extensively drug-resistant variants of the Mycobacterium tuberculosis complex, resistant even to newly discovered and last resort antibiotics, highlight the urgent need for an efficient vaccine. The protective efficacy to pulmonary tuberculosis in adults of the only currently available vaccine, M. bovis BCG, is unsatisfactory and geographically diverse. More importantly, recent clinical studies on new vaccine candidates did not prove to be better than BCG, yet. Here, we propose and discuss novel strategies to improve efficacy of existing anti-tuberculosis vaccines. Modulation of innate immune responses upon vaccination already provided promising results in animal models of tuberculosis. For instance, neutrophils have been shown to influence vaccine efficacy, both, positively and negatively, and stimulate specific antibody secretion. Modulating immune regulatory properties after vaccination such as induction of different types of innate immune cell death, myeloid-derived suppressor or regulatory T cells, production of anti-inflammatory cytokines such as IL-10 may have beneficial effects on protection efficacy. Incorporation of lipid antigens presented via CD1 molecules to T cells have been discussed as a way to enhance vaccine efficacy. Finally, concepts of dendritic cell-based immunotherapies or training the innate immune memory may be exploitable for future vaccination strategies against tuberculosis. In this review, we put a spotlight on host immune networks as potential targets to boost protection by old and new tuberculosis vaccines.

FOXO3 Transcription Factor Regulates IL-10 Expression in Mycobacteria-Infected Macrophages, Tuning Their Polarization and the Subsequent Adaptive Immune Response

“…Inhibition of IL-10 signaling, during BCG vaccination, enhances antigen-specific IFN-γ and IL-17 responses and results in better protection against M.tb challenge (23). These findings demonstrate that modulation of IL-10 at the time of vaccination could be crucial for generating longterm protective efficacy against M.tb (24). Therefore, identifying host effectors that regulate mycobacteria induced IL-10 secretion might be useful for the development of host-directed therapy approaches against M.tb.…”

Colony-stimulating factor-1- and interleukin-34-derived macrophages differ in their susceptibility to Mycobacterium marinum

“…The activation states of host Mϕs critically define susceptibility and resistance to mycobacterial pathogens, in turn dictating the balance between disease progression and infection control . In the present article, we present a previously unexplored facet of Mϕ susceptibility and resistance to mycobacteria, offering an important new perspective into the host Mϕ biology in the context of this infectious agent.…”

Therapeutic host-directed strategies to improve outcome in tuberculosis

“…[123][124][125][126][127][128][129] A comprehensive review by Schaible et al in 2017 evaluates strategies to improve vaccine efficacy against TB by targeting innate INF-γ interferon-γ, TNF-α tumor necrosis factor-α, GM-CSF granulocyte/macrophage-colony stimulating factor, VEGF vascular endothelial growth factor, Ang angiopoietin, IL interleukin, DCs dendritic cells, CD cluster of differentiation, JAK-STAT Janus tyrosine kinase-signal transducer and activator of transcription, TGF-β transforming growth factor-β; BCG = Bacille Calmette Guerin, CFU colony-forming units, MGIT Mycobacteria Growth Indicator Tube a No clinical trial data as evidence for therapeutic intervention potential and outcome in TB disease immunity. 130 Here, they propose that short-term modulation of the local immune response to BCG vaccination may result in longterm protective immunity against Mtb infection. Examples of interventions for such modulation may involve regulating neutrophil, Treg and MDSC recruitment to the vaccination site, preventing disadvantageous cell death pathways, modulating vaccination-induced inflammatory responses, and regulating antiinflammatory cytokine profiles (e.g.…”