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Vaccines
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Research Progress of New Tuberculosis Vaccines and Vaccine Design
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Research Progress of New Tuberculosis Vaccines and Vaccine Design

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

Deadline for manuscript submissions: 31 May 2025 | Viewed by 13447

Special Issue Editors

Dr. Wenping Gong

E-Mail Website1 Website2
Guest Editor
Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
Interests: immunology and immunotherapy; vaccine; Mycobacterium tuberculosis
Special Issues, Collections and Topics in MDPI journals
Dr. Ashok Aspatwar

E-Mail Website
Guest Editor
Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland
Interests: pathogenesis of tuberculosis (TB); develop novel anti-TB drugs targeting alternate pathways of Mycobacterium tuberculosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis infection, and still a global public health problem. Mtb infection can arouse host innate and adaptive immune responses when entering the body. Innate immunity has an important role against Mtb infection. Airway epithelial cells, macrophages, neutrophils, dendritic cells (DCs), natural killer cells (NK), and mast cells, among others, are the major components of innate immunity. The adaptive immunity, including cellular and humoral immune responses, also play important roles against TB. However, although we know the importance of innate and adaptive immune responses against Mtb, the mechanisms behind this need to be further elucidated.

The only licensed vaccine for tuberculosis is the BCG vaccine; however, BCG can only afford partial protection against tuberculosis in children. There is an urgent need for new vaccine development around the world. Current TB vaccine development is mainly based on the following strategies: attenuated live vaccines, subunit vaccines, viral vector vaccines, and inactivated vaccines. Although the M72/AS01E candidate has achieved 49.7% efficacy in TB prevention, there are still some challenges ahead for vaccine research and development: (1) finding more and better animal models for the efficacy evaluation of TB vaccines; (2) elucidating the protective mechanisms of the vaccine candidates including the cellular and antibodies immune responses; (3) improving the efficacy of vaccines licensed in clinical trials; and (4) developing a more efficient, cost-saving, safe, and available TB vaccine.

For this Special Issue of Vaccines, we kindly invite authors to submit an original research article or a review to highlight:

(1) Novel discovery of candidate protective antigens of M. tuberculosis;

(2) The mechanism of the interaction between M. tuberculosis and the host;

(3) The screening, identification, and validation of immunodominant epitopes of M. tuberculosis in silico, vivo, or vitro;

(4) The construction and validation of multi-epitope vaccines for TB prevention;

(5) New bioinformatics or immunoinformatic tools for TB vaccine development;

(6) The trained immunity induced by the BCG vaccine and its potential roles on COVID-19 prevention;

(7) The development of animal models used in TB vaccine evaluation.

Dr. Wenping Gong
Dr. Ashok Aspatwar
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 100 words) can be sent to the Editorial Office for announcement on this website.

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

  • Mycobacterium tuberculosis
  • tuberculosis
  • BCG
  • innate immunity
  • adaptive immunity
  • vaccine development
  • protective immunity

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Published Papers (7 papers)

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Research

20 pages, 4396 KiB  
Article
DNA Subunit Vaccine and Recombinant BCG Based on Mycobacterial Lipoprotein LprO Enhance Anti-Tuberculosis Protection in the Lungs of Mice
by Weili Huang, Shuqin Xu, Lifang Shen, Dan Chen, Hanmei Liu, Yuting Tang, Xiaolin Liu, Wenxuan Xiao, Ziwei Zhou, Shifeng Zhang, Jixi Li, Xiaoyong Fan, Yuefeng Chu and Lu Zhang
Vaccines 2025, 13(4), 400; https://doi.org/10.3390/vaccines13040400 - 11 Apr 2025
Viewed by 384
Abstract
Background/Objectives: Over the past two centuries, tuberculosis (TB) has been responsible for approximately one billion deaths and continues to represent a significant global health challenge. Despite extensive research efforts, fully effective strategies for the prevention or eradication of TB remain elusive, highlighting [...] Read more.
Background/Objectives: Over the past two centuries, tuberculosis (TB) has been responsible for approximately one billion deaths and continues to represent a significant global health challenge. Despite extensive research efforts, fully effective strategies for the prevention or eradication of TB remain elusive, highlighting the urgent demand for novel vaccines with enhanced safety profiles and efficacy. Lipoproteins, integral surface proteins of mycobacteria, are frequently associated with virulence and display notable immunogenicity, rendering them promising candidates for vaccine development. This study investigates the potential of the mycobacterial lipoprotein, LprO, as a vaccine antigen against TB. Methods: A pcDNA-lprO DNA vaccine was constructed, and its immunogenicity was evaluated using a murine model. Its protective efficacy was further assessed using a Mycobacterium marinum (M. marinum)-infected zebrafish model. Additionally, a recombinant BCG vaccine strain, BCG Japan::pNBV1-lprO, was generated. Its immunogenicity was tested in mice, and its safety was evaluated in SCID mice. Both vaccine candidates were further assessed in regard to their protective efficacy in a murine Mycobacterium tuberculosis (M. tb) infection model. Results: The pcDNA-lprO vaccine increased the M. tb-specific IFN-γ-secreting lymphocytes in murine spleens and prolonged the survival of zebrafish infected with M. marinum. The recombinant BCG Japan::pNBV1-lprO vaccine elicited M. tb-specific Th1-type immune responses in mice compared to the standard BCG Japan strain. Both vaccines effectively reduced the bacterial burden of M. tb in murine lungs, offering superior protection relative to the control groups. Conclusions: These findings establish LprO as a compelling candidate for TB vaccine development, with both LprO-based DNA and recombinant BCG vaccines demonstrating robust protective effects against TB. Full article
(This article belongs to the Special Issue Research Progress of New Tuberculosis Vaccines and Vaccine Design)
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11 pages, 2876 KiB  
Article
Bacillus Calmette–Guérin Vaccination Promotes Efficient and Comprehensive Immune Modulation in Guinea Pig Models
by In-Ohk Ouh, Min Jung Kim, Kwangwook Kim, Heeji Lim, Ye Jin Yang, Ji Woong Heo, Han Nim Choi, Hun Hwan Kim, Hu-Jang Lee, Phil-Ok Koh, Seo Young Moon, Eun Bee Choi, Yoo-Kyung Lee and Kwang Il Park
Vaccines 2025, 13(3), 305; https://doi.org/10.3390/vaccines13030305 - 12 Mar 2025
Viewed by 635
Abstract
Background/Objectives: Tuberculosis (TB), caused by Mycobacterium tuberculosis H37Rv (M. tuberculosis), primarily affects the lungs. The Bacillus Calmette–Guérin (BCG) vaccine is the only available TB vaccine. Guinea pigs serve as an excellent preclinical model due to the similarity to human Tuberculosis pathology. [...] Read more.
Background/Objectives: Tuberculosis (TB), caused by Mycobacterium tuberculosis H37Rv (M. tuberculosis), primarily affects the lungs. The Bacillus Calmette–Guérin (BCG) vaccine is the only available TB vaccine. Guinea pigs serve as an excellent preclinical model due to the similarity to human Tuberculosis pathology. However, the lack of a standardized vaccination protocol in guinea pigs causes inconsistencies in efficacy assessments, limiting precise evaluation and its application in vaccine studies. This study aims to address this gap by establishing a consistent and reliable protocol for evaluating the immunological efficacy of BCG vaccination. Methods: Guinea pigs were divided into control, M. tuberculosis-infected, and BCG-vaccinated groups. Four weeks post-vaccination, the infected and vaccinated groups were challenged with M. tuberculosis. The bacterial burden in the lungs and spleen was measured, histopathological changes were analyzed using hematoxylin and eosin (H&E) staining, and the infection levels of M. tuberculosis, as well as the presence of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) positive cells, were evaluated through immunohistochemical (IHC) staining. Results: BCG vaccination reduced the bacterial load to 3.60 × 104 CFU/lung and 5.52 × 103 CFU/spleen compared to 3.78 × 105 CFU/lung and 1.54 × 104 CFU/spleen in the infected group. The mean histopathological score for lungs was 1.67 compared to 2.67 in the infected group. Similarly, the mean histopathological score for the spleen was 1.33 compared to 2.33 in the infected group. IHC analysis showed a notable reduction in M. tuberculosis and inflammatory cytokine-positive cells in the vaccinated group. The TNF-α, IL-2, and IFN-γ staining intensity decreased by 9.3, 4.8, and 11, respectively, compared to the infected group. Conclusions: This protocol enhances consistency in vaccine assessments, providing a reliable benchmark for the development of safer, more effective, and accessible TB vaccines. Full article
(This article belongs to the Special Issue Research Progress of New Tuberculosis Vaccines and Vaccine Design)
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19 pages, 4070 KiB  
Article
A Cap-Optimized mRNA Encoding Multiepitope Antigen ESAT6 Induces Robust Cellular and Humoral Immune Responses Against Mycobacterium tuberculosis
by Alena Kozlova, Ildus Pateev, Galina Shepelkova, Olga Vasileva, Natalia Zakharova, Vladimir Yeremeev, Roman Ivanov and Vasiliy Reshetnikov
Vaccines 2024, 12(11), 1267; https://doi.org/10.3390/vaccines12111267 - 9 Nov 2024
Cited by 1 | Viewed by 1971
Abstract
Background/Objectives. Tuberculosis is a deadly bacterial disease and the second most common cause of death from monoinfectious diseases worldwide. Comprehensive measures taken by health authorities in various countries in recent decades have saved tens of millions of lives, but the number of new [...] Read more.
Background/Objectives. Tuberculosis is a deadly bacterial disease and the second most common cause of death from monoinfectious diseases worldwide. Comprehensive measures taken by health authorities in various countries in recent decades have saved tens of millions of lives, but the number of new cases of this infection has been steadily increasing in the last few years and already exceeds 10 million new cases annually. The development of new vaccines against tuberculosis is a priority area in the prevention of new cases of the disease. mRNA vaccines have already shown high efficacy against COVID-19 and other viral infections and can currently be considered a promising field of antituberculosis vaccination. In our previous study, we assessed the immunogenicity and protective activity of several types of antituberculosis mRNA vaccines with different 5′ untranslated regions, but the efficacy of these vaccines was either comparable with or lower than that of BCG. Methods. Here, we conducted a comprehensive experiment to investigate the effects of cotranscriptional capping conditions and of cap structure on the magnitude of the mRNAs’ translation in HEK293T and DC2.4 cells. The most effective cap version was used to create an antituberculosis mRNA vaccine called mEpitope-ESAT6. Results and Conclusions. We compared immunogenicity and protective activity between mEpitope-ESAT6 and BCG and found that the vaccine with the new cap type is more immunogenic than BCG. Nonetheless, the increased immunogenicity did not enhance vaccine-induced protection. Thus, the incorporation of different cap analogs into mRNA allows to modulate the efficacy of mRNA vaccines. Full article
(This article belongs to the Special Issue Research Progress of New Tuberculosis Vaccines and Vaccine Design)
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11 pages, 3063 KiB  
Article
Enhanced Antimicrobial Peptide Response Following Bacillus Calmette–Guerin Vaccination in Elderly Individuals
by Arul Nancy Pandiarajan, Nathella Pavan Kumar, Anuradha Rajamanickam, Perumal Kannabiran Bhavani, Bharathi Jeyadeepa, Nandhini Selvaraj, Dinesh Asokan, Srikanth Tripathy, Chandrasekharan Padmapriyadarsini and Subash Babu
Vaccines 2024, 12(9), 1065; https://doi.org/10.3390/vaccines12091065 - 18 Sep 2024
Viewed by 1210
Abstract
Background: Antimicrobial peptides are an important component of host defense against Mycobacterium tuberculosis. However, the ability of BCG to induce AMPs as part of its mechanism of action has not been investigated in detail. Methods: We investigated the impact of Bacillus Calmette–Guerin (BCG) [...] Read more.
Background: Antimicrobial peptides are an important component of host defense against Mycobacterium tuberculosis. However, the ability of BCG to induce AMPs as part of its mechanism of action has not been investigated in detail. Methods: We investigated the impact of Bacillus Calmette–Guerin (BCG) vaccination on circulating plasma levels and TB-antigen stimulated plasma levels of AMPs in a healthy elderly population. We assessed the association of AMPs, including Human Beta Defensin 2 (HBD-2), Human Neutrophil Peptide 1-3 (HNP1-3), Granulysin, and Cathelicidin (LL37), in circulating plasma and TB-antigen stimulated plasma (using IGRA supernatants) at baseline (pre-vaccination) and at Month 1 and Month 6 post vaccination. Results: Post BCG vaccination, both circulating plasma levels and TB-antigen stimulated plasma levels of AMPs significantly increased at Month 1 and Month 6 compared to pre-vaccination levels in the elderly population. However, the association of AMP levels with latent TB (LTB) status did not exhibit statistical significance. Conclusion: Our findings indicate that BCG vaccination is linked to heightened circulating levels of AMPs in the elderly population, which are also TB-antigen-specific. This suggests a potential mechanism underlying the immune effects of BCG in enhancing host defense against TB. Full article
(This article belongs to the Special Issue Research Progress of New Tuberculosis Vaccines and Vaccine Design)
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16 pages, 4495 KiB  
Article
Safety and Immunogenicity of an In Vivo Muscle Electroporation Delivery System for DNA-hsp65 Tuberculosis Vaccine in Cynomolgus Monkeys
by Monique Ribeiro de Lima, Ana Cristina C. S. Leandro, Andreia Lamoglia de Souza, Marcio Mantuano Barradas, Eric Henrique Roma, Ana Teresa Gomes Fernandes, Gabrielle Galdino-Silva, Joyce Katiuccia M. Ramos Carvalho, Renato Sergio Marchevsky, Janice M. C. Oliveira Coelho, Eduardo Dantas Casillo Gonçalves, John L. VandeBerg, Celio Lopes Silva and Maria da Gloria Bonecini-Almeida
Vaccines 2023, 11(12), 1863; https://doi.org/10.3390/vaccines11121863 - 18 Dec 2023
Cited by 1 | Viewed by 2315
Abstract
A Bacille Calmette–Guérin (BCG) is still the only licensed vaccine for the prevention of tuberculosis, providing limited protection against Mycobacterium tuberculosis infection in adulthood. New advances in the delivery of DNA vaccines by electroporation have been made in the past decade. We evaluated [...] Read more.
A Bacille Calmette–Guérin (BCG) is still the only licensed vaccine for the prevention of tuberculosis, providing limited protection against Mycobacterium tuberculosis infection in adulthood. New advances in the delivery of DNA vaccines by electroporation have been made in the past decade. We evaluated the safety and immunogenicity of the DNA-hsp65 vaccine administered by intramuscular electroporation (EP) in cynomolgus macaques. Animals received three doses of DNA-hsp65 at 30-day intervals. We demonstrated that intramuscular electroporated DNA-hsp65 vaccine immunization of cynomolgus macaques was safe, and there were no vaccine-related effects on hematological, renal, or hepatic profiles, compared to the pre-vaccination parameters. No tuberculin skin test conversion nor lung X-ray alteration was identified. Further, low and transient peripheral cellular immune response and cytokine expression were observed, primarily after the third dose of the DNA-hsp65 vaccine. Electroporated DNA-hsp65 vaccination is safe but provides limited enhancement of peripheral cellular immune responses. Preclinical vaccine trials with DNA-hsp65 delivered via EP may include a combination of plasmid cytokine adjuvant and/or protein prime–boost regimen, to help the induction of a stronger cellular immune response. Full article
(This article belongs to the Special Issue Research Progress of New Tuberculosis Vaccines and Vaccine Design)
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26 pages, 26570 KiB  
Article
PP19128R, a Multiepitope Vaccine Designed to Prevent Latent Tuberculosis Infection, Induced Immune Responses In Silico and In Vitro Assays
by Fan Jiang, Cong Peng, Peng Cheng, Jie Wang, Jianqi Lian and Wenping Gong
Vaccines 2023, 11(4), 856; https://doi.org/10.3390/vaccines11040856 - 17 Apr 2023
Cited by 20 | Viewed by 2829
Abstract
Background: Latent tuberculosis infection (LTBI) is the primary source of active tuberculosis (ATB), but a preventive vaccine against LTBI is lacking. Methods: In this study, dominant helper T lymphocyte (HTL), cytotoxic T lymphocyte (CTL), and B-cell epitopes were identified from nine antigens related [...] Read more.
Background: Latent tuberculosis infection (LTBI) is the primary source of active tuberculosis (ATB), but a preventive vaccine against LTBI is lacking. Methods: In this study, dominant helper T lymphocyte (HTL), cytotoxic T lymphocyte (CTL), and B-cell epitopes were identified from nine antigens related to LTBI and regions of difference (RDs). These epitopes were used to construct a novel multiepitope vaccine (MEV) based on their antigenicity, immunogenicity, sensitization, and toxicity. The immunological characteristics of the MEV were analyzed with immunoinformatics technology and verified by enzyme-linked immunospot assay and Th1/Th2/Th17 cytokine assay in vitro. Results: A novel MEV, designated PP19128R, containing 19 HTL epitopes, 12 CTL epitopes, 8 B-cell epitopes, toll-like receptor (TLR) agonists, and helper peptides, was successfully constructed. Bioinformatics analysis showed that the antigenicity, immunogenicity, and solubility of PP19128R were 0.8067, 9.29811, and 0.900675, respectively. The global population coverage of PP19128R in HLA class I and II alleles reached 82.24% and 93.71%, respectively. The binding energies of the PP19128R-TLR2 and PP19128R-TLR4 complexes were −1324.77 kcal/mol and −1278 kcal/mol, respectively. In vitro experiments showed that the PP19128R vaccine significantly increased the number of interferon gamma-positive (IFN-γ+) T lymphocytes and the levels of cytokines, such as IFN-γ, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10. Furthermore, positive correlations were observed between PP19128R-specific cytokines in ATB patients and individuals with LTBI. Conclusions: The PP19128R vaccine is a promising MEV with excellent antigenicity and immunogenicity and no toxicity or sensitization that can induce robust immune responses in silico and in vitro. This study provides a vaccine candidate for the prevention of LTBI in the future. Full article
(This article belongs to the Special Issue Research Progress of New Tuberculosis Vaccines and Vaccine Design)
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16 pages, 2368 KiB  
Article
A Multistage Antigen Complex Epera013 Promotes Efficient and Comprehensive Immune Responses in BALB/c Mice
by Chengyu Qian, Xueting Fan, Ruihuan Wang, Bin Cao, Jinjie Yu, Xiuli Luan, Guilian Li, Yi Jiang, Machao Li, Xiuqin Zhao, Danang Fang, Kanglin Wan, Haican Liu and Yongliang Lou
Vaccines 2023, 11(3), 609; https://doi.org/10.3390/vaccines11030609 - 7 Mar 2023
Cited by 1 | Viewed by 2539
Abstract
Tuberculosis (TB) remains a serious global health problem. Despite the widespread use of the Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine, the primary factor for the TB pandemic and deaths is adult TB, which mainly result from endogenous reactivation of latent Mycobacterium tuberculosis (MTB) [...] Read more.
Tuberculosis (TB) remains a serious global health problem. Despite the widespread use of the Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine, the primary factor for the TB pandemic and deaths is adult TB, which mainly result from endogenous reactivation of latent Mycobacterium tuberculosis (MTB) infection. Improved new TB vaccines with eligible safety and long-lasting protective efficacy remains a crucial step toward the prevention and control of TB. In this study, five immunodominant antigens, including three early secreted antigens and two latency associated antigens, were used to construct a single recombinant fusion protein (Epera013f) and a protein mixture (Epera013m). When formulated with aluminum adjuvant, the two subunit vaccines Epera013m and Epera013f were administered to BALB/c mice. The humoral immune responses, cellular responses and MTB growth inhibiting capacity elicited after Epera013m and Epera013f immunization were analyzed. In the present study, we demonstrated that both the Epera013f and Epera013m were capable of inducing a considerable immune response and protective efficacy against H37Rv infection compared with BCG groups. In addition, Epera013f generated a more comprehensive and balanced immune status, including Th1, Th2 and innate immune response, over Epera013f and BCG. The multistage antigen complex Epera013f possesses considerable immunogenicity and protective efficacy against MTB infection ex vivo indicating its potential and promising applications in further TB vaccine development. Full article
(This article belongs to the Special Issue Research Progress of New Tuberculosis Vaccines and Vaccine Design)
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