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BCG Vaccine and Beyond: Innovations in Tuberculosis Vaccination and Inflammation-Related...
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BCG Vaccine and Beyond: Innovations in Tuberculosis Vaccination and Inflammation-Related Disease Prevention

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccines against Infectious Diseases".

Deadline for manuscript submissions: 28 February 2027 | Viewed by 5239

Special Issue Editors

Prof. Dr. Xiao-Yong Fan

E-Mail Website
Guest Editor
Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai, China
Interests: Mycobacterium tuberculosis; BCG; vaccine; infection and immunity; tuberculosis; diagonosis; trained immunity; immunotherapy
Prof. Dr. Zhi-Dong Hu

E-Mail Website
Guest Editor
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Interests: tuberculosis; vaccine; adaptive immunity; trained immunity; innate immune memory; alevolar macrophage

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) remains one of the deadliest infectious diseases globally, claiming over 1.3 million lives annually despite decades of research and public health efforts. The Bacillus Calmette–Guérin (BCG) vaccine, developed a century ago, provides partial protection against severe forms of childhood TB, but has limited efficacy in preventing pulmonary TB in adolescents and adults. There is an urgent need to accelerate the development and deployment of next-generation TB vaccines. Recent advances in immunology, genomics, and vaccine delivery systems have reignited hope for achieving the WHO’s End TB Strategy targets. This Special Issue seeks to consolidate cutting-edge research and foster interdisciplinary collaboration to address critical gaps in TB vaccine science and implementation. We are pleased to invite you to contribute to this Special Issue focused on “Tuberculosis Vaccines and Vaccination”.

This Special Issue aims to gather articles presenting state-of-the-art research, novel discoveries, and the latest progress of novel tuberculosis vaccines and vaccination in pre-clinical and clinical studies.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  1. Novel approaches to improve the protective efficacy of current TB vaccines;
  2. Novel vaccine delivery methods;
  3. Novel insights and approaches to TB vaccine development in pre-clinical and clinical studies;
  4. Immune correlates of protection studies in tuberculosis vaccine research;
  5. The role of vaccine-induced innate immune memory in tuberculosis vaccines;
  6. The role of tissue-resident memory cells in tuberculosis vaccines.

We look forward to receiving your contributions.

Prof. Dr. Xiao-Yong Fan
Prof. Dr. Zhi-Dong Hu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tuberculosis
  • vaccine
  • vaccination
  • immune response
  • adjuvant
  • T-cell
  • immune memory
  • adaptive immunity
  • innate immune memory
  • correlates of protection

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Published Papers (4 papers)

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Research

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21 pages, 2326 KB  
Article
Immunogenicity and Protective Effects of an Ag85B Tuberculosis Subunit Vaccine Formulated with Synthetic TLR4 Agonists in BCG-Boosted Mice
by Soo-Min Kim, Jin-Seung Yun, EunJung Shin, Jinhee Lee, You-Jin Kim, Hye-Sook Jeong, Yong Woo Jung and Dokeun Kim
Vaccines 2026, 14(3), 214; https://doi.org/10.3390/vaccines14030214 - 26 Feb 2026
Viewed by 935
Abstract
Background/Objectives: Tuberculosis (TB) remains a major global health challenge, and the Bacillus Calmette–Guérin (BCG) vaccine has limited efficacy against adult pulmonary disease. Protein subunit vaccines are a promising alternative but require strong adjuvants to induce cell-mediated immunity. Synthetic agonists targeting toll-like receptor 4 [...] Read more.
Background/Objectives: Tuberculosis (TB) remains a major global health challenge, and the Bacillus Calmette–Guérin (BCG) vaccine has limited efficacy against adult pulmonary disease. Protein subunit vaccines are a promising alternative but require strong adjuvants to induce cell-mediated immunity. Synthetic agonists targeting toll-like receptor 4 (TLR4) and stimulators of interferon genes (STINGs) have emerged as effective immunostimulants. Therefore, we aimed to evaluate the immunogenicity and protective efficacy of Ag85B-based subunit vaccines formulated with synthetic TLR4 and STING agonists in a BCG-boosted mouse model. Methods: Three synthetic adjuvants—QTP709-1, QTP709-3, and QTP701—were formulated as oil-in-water emulsions containing distinct surfactant and immunostimulant components. The potential of vaccine formulations to activate dendritic cells (DCs) and elicit Ag85B-specific immune responses, including IgG subclass levels, interferon-γ (IFN-γ) enzyme-linked immunosorbent spots, and polyfunctional T-cell responses, was assessed by flow cytometry. Protective efficacy was evaluated based on pulmonary bacterial burden and histopathology following Mycobacterium tuberculosis (M. tb) Erdman challenge. Results: All formulations promoted DC maturation and enhanced antigen-specific immune responses. Each adjuvant elicited strong Ag85B-specific humoral immunity, increased IFN-γ secretion, and polyfunctional CD4+ and CD8+ T cells co-producing IFN-γ, TNF-α, and interleukin-2. Among them, QTP709-1 was associated with increased levels of chemokine receptor 5-associated chemokines and showed a trend toward reduced lung bacterial burden and histopathological inflammation following M. tb challenge. Conclusions: Synthetic TLR4 and STING agonists were associated with enhanced immunogenicity of TB subunit vaccines and showed evidence of protective potential, with TLR4-based formulations exhibiting more pronounced immunological responses. QTP709-1 exhibited strong immunostimulatory and protective effects, supporting its potential as a candidate adjuvant for next-generation TB vaccines. Full article
(This article belongs to the Special Issue BCG Vaccine and Beyond: Innovations in Tuberculosis Vaccination and Inflammation-Related Disease Prevention)
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15 pages, 6048 KB  
Article
Mucosal Adenovirus-Vectored Rv2299c Vaccine Protects Against Tuberculosis by Inducing Trained Immunity in Dendritic Cells and Polyfunctional T Cells
by Huiling Wang, Shiqi Xie, Shaoqiong Huang, Xuejiao Huang, Ying Zhang, Juan Wu, Xiao-Yong Fan and Zhidong Hu
Vaccines 2026, 14(1), 55; https://doi.org/10.3390/vaccines14010055 - 2 Jan 2026
Cited by 1 | Viewed by 1061
Abstract
Background: The development of effective tuberculosis (TB) vaccines beyond BCG remains an urgent global health priority, especially for prevention of pulmonary TB in adults. While most current strategies focus on enhancing T-cell immunity, the potential of trained immunity to broadly augment both [...] Read more.
Background: The development of effective tuberculosis (TB) vaccines beyond BCG remains an urgent global health priority, especially for prevention of pulmonary TB in adults. While most current strategies focus on enhancing T-cell immunity, the potential of trained immunity to broadly augment both innate and adaptive responses remains underexplored in TB vaccinology. Given the central role of dendritic cells (DCs) as bridges between innate and adaptive immunity, we hypothesized that inducing trained immunity in DCs could optimize subsequent T-cell responses. Previous studies have identified Rv2299c as a promising adjuvant of other antigens by promoting DC maturation; however, whether it could be used as a standalone protective antigen of TB vaccine remains unclear. Methods: We constructed a chimpanzee adenovirus-vectored TB vaccine candidate expressing Rv2299c (rAd-Rv2299c), and evaluated its immunogenicity and protective efficacy in murine models. Results: rAd-Rv2299c vaccine effectively induced a trained immunity phenotype in DCs, as evidenced by upregulated MHC-II and CD86 expression and increased pro-inflammatory cytokine (TNF-α, IL-6, IL-1β and IL-12p70) secretion. Moreover, its immunization promoted the generation of antigen-specific polyfunctional T cells, and robustly enhanced both Th1 and Th17-type immune responses. In a murine challenge model, vaccination significantly reduced bacterial loads in the lung and spleen and attenuated pulmonary inflammation, which was associated with robust recall T-cell immune responses. Conclusions: rAd-Rv2299c confers anti-TB protection by inducing trained immunity in DCs and promoting polyfunctional T-cell responses, thereby offering valuable experimental evidence and conceptual insights for the development of next-generation TB vaccines. Full article
(This article belongs to the Special Issue BCG Vaccine and Beyond: Innovations in Tuberculosis Vaccination and Inflammation-Related Disease Prevention)
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Review

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28 pages, 1515 KB  
Review
Bacillus Calmette–Guérin (BCG) Vaccination and the Immune–Brain Axis: Implications for Neuroprotection and Neurodegenerative Disease
by Magdalena Druszczynska, Beata Sadowska, Jakub Kulesza, Ewelina Kulesza and Marek Fol
Vaccines 2026, 14(5), 412; https://doi.org/10.3390/vaccines14050412 - 2 May 2026
Viewed by 585
Abstract
The Bacillus Calmette–Guérin (BCG) vaccine, originally developed for tuberculosis (TB) prevention, has recently attracted attention due to its broader immunomodulatory properties. In addition to its role in TB control, BCG induces trained immunity, a process involving epigenetic and metabolic reprogramming of innate immune [...] Read more.
The Bacillus Calmette–Guérin (BCG) vaccine, originally developed for tuberculosis (TB) prevention, has recently attracted attention due to its broader immunomodulatory properties. In addition to its role in TB control, BCG induces trained immunity, a process involving epigenetic and metabolic reprogramming of innate immune cells that leads to altered systemic inflammatory responses. Increasing evidence suggests that these long-term immune adaptations may influence the central nervous system by modulating microglial activation and neuroinflammatory pathways implicated in neurodegenerative diseases. In parallel, chronic infections such as TB are associated with persistent systemic inflammation and immune dysregulation, which may contribute to microglial priming and increased vulnerability to neurodegeneration. This narrative review, based on a targeted literature search of PubMed, Scopus, Web of Science, Embase, and relevant preprint servers, synthesizes current evidence on the relationships between BCG vaccination, trained immunity, and neuroimmune interactions. We focus on studies addressing systemic immune reprogramming, microglial responses, and neuroinflammatory mechanisms relevant to neurodegenerative disorders. The available data suggest that BCG-induced immune modulation may exert context-dependent effects on the brain, with potential neuroprotective implications under certain conditions. However, the evidence remains heterogeneous and largely observational, and causality cannot yet be established. Further mechanistic and prospective studies are required to clarify whether BCG-induced trained immunity can modify the risk or progression of age-related neurodegenerative diseases. Full article
(This article belongs to the Special Issue BCG Vaccine and Beyond: Innovations in Tuberculosis Vaccination and Inflammation-Related Disease Prevention)
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23 pages, 2140 KB  
Review
Stopping Tuberculosis at the Gate: The Role of M. tuberculosis Adhesins in Infection and Intervention
by Haoyan Yang, Yinuo Ma, Xinkui Lei, Siyu Chai, Sigen Zhang, Guimin Su, Songping Li and Lin Du
Vaccines 2025, 13(7), 676; https://doi.org/10.3390/vaccines13070676 - 24 Jun 2025
Cited by 2 | Viewed by 1961
Abstract
The global burden of tuberculosis (TB), exacerbated by the rise of drug-resistant Mycobacterium tuberculosis (M. tuberculosis), underscores the need for alternative intervention strategies. One promising approach is to block the infection at its earliest stage—bacterial adhesion to host cells—thereby preventing colonization [...] Read more.
The global burden of tuberculosis (TB), exacerbated by the rise of drug-resistant Mycobacterium tuberculosis (M. tuberculosis), underscores the need for alternative intervention strategies. One promising approach is to block the infection at its earliest stage—bacterial adhesion to host cells—thereby preventing colonization and transmission without exerting selective pressure. Adhesins, surface-exposed molecules mediating this critical interaction, have therefore emerged as attractive targets for early prevention. This review outlines the infection process driven by bacterial adhesion and describes the architecture of the M. tuberculosis outer envelope, emphasizing components that contribute to host interaction. We comprehensively summarize both non-protein and protein adhesins, detailing their host receptors, biological roles, and experimental evidence. Recent progress in the computational prediction of adhesins, particularly neural network-based tools like SPAAN, is also discussed, highlighting its potential to accelerate adhesin discovery. Additionally, we present a detailed, generalized workflow for predicting M. tuberculosis adhesins, which synthesizes current approaches and provides a comprehensive framework for future studies. Targeting bacterial adhesion presents a therapeutic strategy that interferes with the early stages of infection while minimizing the risk of developing drug resistance. Consequently, anti-adhesion strategies may serve as valuable complements to conventional therapies and support the development of next-generation TB vaccines and treatments. Full article
(This article belongs to the Special Issue BCG Vaccine and Beyond: Innovations in Tuberculosis Vaccination and Inflammation-Related Disease Prevention)
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