Research Topic

Beyond Th1: Novel Concepts in tuberculosis vaccine immunology

About this Research Topic

2021 marks the 100-year anniversary of the first application of Bacillus Calmette Guerin (BCG) in humans, the only licensed tuberculosis (TB) vaccine to date. Throughout the years, this attenuated strain of Mycobacterium bovis has protected numerous infants from death and disability due to severe forms of pediatric tuberculosis. However, it fails to reliably protect adolescents and adults from pulmonary TB and is thus ineffective in curbing the ongoing TB epidemic. The need for a new, more effective TB vaccine is urgent. Annually, approximately 1,5 million individuals continue to die from TB and a further 10 million individuals fall ill with the disease. The WHO has made a 95% reduction in TB incidence one of its goals for 2035 and deems an effective vaccine indispensable for reaching this goal.

Unfortunately, the development of more effective TB vaccines has been hampered by a lack of knowledge on what protective immunity against TB exactly requires. Historically, vaccine developers have optimized their candidate vaccines towards the induction of peripheral Interferon-γ (IFNγ) producing T-helper type 1 (Th1) cells. The importance of this Th1-response is supported by the increased susceptibility to mycobacterial infection in individuals with inborn errors interfering with the production of IFNγ or Interleukin-12, as well as the increased risk of development of TB in HIV patients with a low CD4 T-cell count. However, mounting evidence generated in animal models, clinical trials, and cohort studies suggests that a Th1 response is not solely sufficient for (vaccine-mediated) protection from tuberculosis.

In recent years, a plethora of new immune subsets and concepts have been studied and implicated in the context of protection from TB. Notable examples include Donor Unrestricted T-cells (DURTs), T-helper 17 cells, and while previously deemed redundant, antibodies and B-cells. Also innate immune players, including myeloid suppressor cells, may be more pivotal than originally anticipated. Furthermore, the potential of pulmonary, tissue-resident immune responses as rapid responders to TB infection is increasingly appreciated, and mucosal delivery of vaccines to induce these responses is currently being investigated.

The accelerated development of multiple, highly effective vaccines in the wake of the COVID-19 pandemic, has incited a push for a similar effort towards a novel, more effective TB vaccine. The shift in focus of the TB vaccine field allows for diversification in the development of candidate TB vaccines, maximizing the chance of an efficacious TB vaccine regimen. In this Research Topic, we aim to generate a collection of articles on vaccine-concepts beyond the induction of peripheral Th1 immunity that add to our knowledge on protective immunity and will advance the field of TB vaccine development. Potential topics include, but are not limited to:
- The role of the innate immune system and innate immune training in vaccine-mediated protection against TB
- Protection mediated by adaptive immune responses other than T-helper type 1 T-cells in TB infection
- The induction and maintenance of more differentiated T cells, such as circulating effector T-cells, and tissue resident T-cells through vaccination to prevent TB infection and/or disease
- Alternative/novel vaccine delivery strategies and routes for TB vaccination, including RNA vaccines
- Novel adjuvants for TB vaccines that skew towards responses other than Th1
- Combining (post-exposure) vaccination with host-directed therapy for TB treatment and prophylaxis
- CD8+ responses in protection from TB.
- Contribution of the humoral immune response in protective immunity to TB, including antibody glycosylation, B cell follicles in TB granulomas and T follicular helper cell responses in TB infection.

We welcome the submission of various article types, including Original Research, Reviews, Perspectives and Clinical Trials articles.


Keywords: tuberculosis, vaccines, immunity


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

2021 marks the 100-year anniversary of the first application of Bacillus Calmette Guerin (BCG) in humans, the only licensed tuberculosis (TB) vaccine to date. Throughout the years, this attenuated strain of Mycobacterium bovis has protected numerous infants from death and disability due to severe forms of pediatric tuberculosis. However, it fails to reliably protect adolescents and adults from pulmonary TB and is thus ineffective in curbing the ongoing TB epidemic. The need for a new, more effective TB vaccine is urgent. Annually, approximately 1,5 million individuals continue to die from TB and a further 10 million individuals fall ill with the disease. The WHO has made a 95% reduction in TB incidence one of its goals for 2035 and deems an effective vaccine indispensable for reaching this goal.

Unfortunately, the development of more effective TB vaccines has been hampered by a lack of knowledge on what protective immunity against TB exactly requires. Historically, vaccine developers have optimized their candidate vaccines towards the induction of peripheral Interferon-γ (IFNγ) producing T-helper type 1 (Th1) cells. The importance of this Th1-response is supported by the increased susceptibility to mycobacterial infection in individuals with inborn errors interfering with the production of IFNγ or Interleukin-12, as well as the increased risk of development of TB in HIV patients with a low CD4 T-cell count. However, mounting evidence generated in animal models, clinical trials, and cohort studies suggests that a Th1 response is not solely sufficient for (vaccine-mediated) protection from tuberculosis.

In recent years, a plethora of new immune subsets and concepts have been studied and implicated in the context of protection from TB. Notable examples include Donor Unrestricted T-cells (DURTs), T-helper 17 cells, and while previously deemed redundant, antibodies and B-cells. Also innate immune players, including myeloid suppressor cells, may be more pivotal than originally anticipated. Furthermore, the potential of pulmonary, tissue-resident immune responses as rapid responders to TB infection is increasingly appreciated, and mucosal delivery of vaccines to induce these responses is currently being investigated.

The accelerated development of multiple, highly effective vaccines in the wake of the COVID-19 pandemic, has incited a push for a similar effort towards a novel, more effective TB vaccine. The shift in focus of the TB vaccine field allows for diversification in the development of candidate TB vaccines, maximizing the chance of an efficacious TB vaccine regimen. In this Research Topic, we aim to generate a collection of articles on vaccine-concepts beyond the induction of peripheral Th1 immunity that add to our knowledge on protective immunity and will advance the field of TB vaccine development. Potential topics include, but are not limited to:
- The role of the innate immune system and innate immune training in vaccine-mediated protection against TB
- Protection mediated by adaptive immune responses other than T-helper type 1 T-cells in TB infection
- The induction and maintenance of more differentiated T cells, such as circulating effector T-cells, and tissue resident T-cells through vaccination to prevent TB infection and/or disease
- Alternative/novel vaccine delivery strategies and routes for TB vaccination, including RNA vaccines
- Novel adjuvants for TB vaccines that skew towards responses other than Th1
- Combining (post-exposure) vaccination with host-directed therapy for TB treatment and prophylaxis
- CD8+ responses in protection from TB.
- Contribution of the humoral immune response in protective immunity to TB, including antibody glycosylation, B cell follicles in TB granulomas and T follicular helper cell responses in TB infection.

We welcome the submission of various article types, including Original Research, Reviews, Perspectives and Clinical Trials articles.


Keywords: tuberculosis, vaccines, immunity


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

22 August 2021 Abstract
20 December 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

22 August 2021 Abstract
20 December 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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