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Pharmaceutics
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Tuberculosis Vaccine Research and Development
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Tuberculosis Vaccine Research and Development

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (3 July 2020) | Viewed by 17570

Special Issue Editor

Prof. Dr. Mark Chambers

E-Mail Website1 Website2
Guest Editor
Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
Interests: antimicrobial resistance; animal-alternative laboratory models of host–pathogen interaction; disease interventions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tuberculosis is one of the biggest threats to the health, welfare, and productivity of humans and animals globally. It causes more human deaths than any other infectious organism. The prevalence of antibiotic resistance among human cases and the cost and logistical challenges associated with controlling the disease in animals make a compelling case for continued efforts to employ a vaccination in combatting the disease.

While a vaccine for tuberculosis in the form of Bacillus Calmette–Guérin (BCG) has been around for nearly a century, it is not universally effective in people and is rarely used in animals. The World Health Organisation (WHO) has the ambitious aim of ending the global tuberculosis epidemic by 2030. It is now recognized that this is unlikely unless tuberculosis in animals is also addressed at the same time.

Progress with vaccination against tuberculosis is both difficult and slow and many hurdles remain. These include (1) identifying a more efficacious prophylactic vaccine than BCG alone; (2) a vaccine that can be used post-exposure to contain or remove the latent infection with tuberculosis, thought to exist in a third of the world’s population; and (3) vaccines and associated diagnostic tests for use in animals. A clear roadmap towards identifying, testing, licensing, and deploying such vaccines is required, together with sustained funding at a global level.

This Special Issue will highlight current research activities in the research and development of tuberculosis vaccines. We particularly encourage submissions relating to vaccine formulation (such as DNA, subunit, recombinant, and nano- and micro-particles) and different delivery modalities (such as mucosal, aerosol, transdermal) and the evaluation of their safety and efficacy in animal models and target species. 

Prof. Mark Chambers
Guest Editor

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. Pharmaceutics 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 2900 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
  • Vaccination
  • Prophylaxis
  • Therapy
  • Safety
  • Efficacy

Published Papers (5 papers)

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Research

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14 pages, 1520 KiB  
Article
Optimisation of Mycobacterium bovis BCG Fermentation and Storage Survival
by Jordan Pascoe, Charlotte L. Hendon-Dunn, Colin P.D. Birch, Gareth A. Williams, Mark A. Chambers and Joanna Bacon
Pharmaceutics 2020, 12(9), 900; https://doi.org/10.3390/pharmaceutics12090900 - 22 Sep 2020
Cited by 4 | Viewed by 3360
Abstract
Mycobacterium bovis Bacillus Calmette–Guérin (M. bovis BCG) was generated over a century ago for protection against Mycobacterium tuberculosis (Mtb) and is one the oldest vaccines still in use. The BCG vaccine is currently produced using a pellicle growth method, which is a [...] Read more.
Mycobacterium bovis Bacillus Calmette–Guérin (M. bovis BCG) was generated over a century ago for protection against Mycobacterium tuberculosis (Mtb) and is one the oldest vaccines still in use. The BCG vaccine is currently produced using a pellicle growth method, which is a complex and lengthy process that has been challenging to standardise. Fermentation for BCG vaccine production would reduce the complexity associated with pellicle growth and increase batch to batch reproducibility. This more standardised growth lends itself to quantification of the total number of bacilli in the BCG vaccine by alternative approaches, such as flow cytometry, which can also provide information about the metabolic status of the bacterial population. The aim of the work reported here was to determine which batch fermentation conditions and storage conditions give the most favourable outcomes in terms of the yield and stability of live M. bovis BCG Danish bacilli. We compared different media and assessed growth over time in culture, using total viable counts, total bacterial counts, and turbidity throughout culture. We applied fluorescent viability dyes and flow cytometry to measure real-time within-culture viability. Culture samples were stored in different cryoprotectants at different temperatures to assess the effect of these combined conditions on bacterial titres. Roisin’s minimal medium and Middlebrook 7H9 medium gave comparable, high titres in fermenters. Flow cytometry proved to be a useful tool for enumeration of total bacterial counts and in the assessment of within-culture cell viability and cell death. Of the cryoprotectants evaluated, 5% (v/v) DMSO showed the most significant positive effect on survival and reduced the negative effects of low temperature storage on M. bovis BCG Danish viability. In conclusion, we have shown a reproducible, more standardised approach for the production, evaluation, and storage of high titre, viable, BCG vaccine. Full article
(This article belongs to the Special Issue Tuberculosis Vaccine Research and Development)
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23 pages, 1577 KiB  
Article
Bioreactor-Grown Bacillus of Calmette and Guérin (BCG) Vaccine Protects Badgers against Virulent Mycobacterium bovis When Administered Orally: Identifying Limitations in Baited Vaccine Delivery
by Sandrine Lesellier, Colin P. D. Birch, Dipesh Davé, Deanna Dalley, Sonya Gowtage, Simonette Palmer, Claire McKenna, Gareth A. Williams, Roland Ashford, Ute Weyer, Sarah Beatham, Julia Coats, Alex Nunez, Pedro Sanchez-Cordon, John Spiropoulos, Stephen Powell, Jason Sawyer, Jordan Pascoe, Charlotte Hendon-Dunn, Joanna Bacon and Mark A. Chambersadd Show full author list remove Hide full author list
Pharmaceutics 2020, 12(8), 782; https://doi.org/10.3390/pharmaceutics12080782 - 18 Aug 2020
Cited by 9 | Viewed by 3364
Abstract
Bovine tuberculosis (TB) in Great Britain adversely affects animal health and welfare and is a cause of considerable economic loss. The situation is exacerbated by European badgers (Meles meles) acting as a wildlife source of recurrent Mycobacterium bovis infection to cattle. [...] Read more.
Bovine tuberculosis (TB) in Great Britain adversely affects animal health and welfare and is a cause of considerable economic loss. The situation is exacerbated by European badgers (Meles meles) acting as a wildlife source of recurrent Mycobacterium bovis infection to cattle. Vaccination of badgers against TB is a possible means to reduce and control bovine TB. The delivery of vaccine in oral bait holds the best prospect for vaccinating badgers over a wide geographical area. There are practical limitations over the volume and concentration of Bacillus of Calmette and Guérin (BCG) that can be prepared for inclusion in bait. The production of BCG in a bioreactor may overcome these issues. We evaluated the efficacy of oral, bioreactor-grown BCG against experimental TB in badgers. We demonstrated repeatable protection through the direct administration of at least 2.0 × 108 colony forming units of BCG to the oral cavity, whereas vaccination via voluntary consumption of bait containing the same preparation of BCG did not result in demonstrable protection at the group-level, although a minority of badgers consuming bait showed immunological responses and protection after challenge equivalent to badgers receiving oral vaccine by direct administration. The need to deliver oral BCG in the context of a palatable and environmentally robust bait appears to introduce such variation in BCG delivery to sites of immune induction in the badger as to render experimental studies variable and inconsistent. Full article
(This article belongs to the Special Issue Tuberculosis Vaccine Research and Development)
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22 pages, 4919 KiB  
Article
Design of Polymeric Nanocapsules for Intranasal Vaccination against Mycobacterium Tuberculosis: Influence of the Polymeric Shell and Antigen Positioning
by Lara Diego-González, José Crecente-Campo, Matthew John Paul, Mahavir Singh, Rajko Reljic, María José Alonso, África González-Fernández and Rosana Simón-Vázquez
Pharmaceutics 2020, 12(6), 489; https://doi.org/10.3390/pharmaceutics12060489 - 28 May 2020
Cited by 19 | Viewed by 3163
Abstract
Tuberculosis (TB) is the leading cause of death from a single infectious microorganism and Bacillus Calmette Guerin (BCG), the only authorized vaccine, does not confer protection against pulmonary TB. Based on the hypothesis that mucosal protection could help to prevent the infection at [...] Read more.
Tuberculosis (TB) is the leading cause of death from a single infectious microorganism and Bacillus Calmette Guerin (BCG), the only authorized vaccine, does not confer protection against pulmonary TB. Based on the hypothesis that mucosal protection could help to prevent the infection at the site of entrance, the objective of this work was to develop an intranasal vaccine against Mycobacterium tuberculosis (Mtb), the microorganism that causes TB. Our approach consisted of the use of polymeric nanocapsules (NCs) with an oily core and a polymer shell made of chitosan (CS) or inulin/polyarginine (INU/pArg). The immunostimulant Imiquimod, a Toll-like receptor-7 (TLR-7) agonist, was encapsulated in the oily core and a fusion protein, formed by two antigens of Mtb, was absorbed either onto the NC surface (CS:Ag and INU:pArg:Ag) or between two polymer layers (INU:Ag:pArg) in order to assess the influence of the antigen positioning on the immune response. Although CS NCs were more immunostimulant than the INU/pArg NCs in vitro, the in vivo experiments showed that INU:pArg:Ag NCs were the only prototype inducing an adequate immunoglobulin A (IgA) response. Moreover, a previous immunization with BCG increased the immune response for CS NCs but, conversely, decreased for INU/pArg NCs. Further optimization of the antigen and the vaccination regime could provide an efficacious vaccine, using the INU:pArg:Ag NC prototype as nanocarrier. Full article
(This article belongs to the Special Issue Tuberculosis Vaccine Research and Development)
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25 pages, 4195 KiB  
Article
Protective Efficacy of Inhaled BCG Vaccination Against Ultra-Low Dose Aerosol M. tuberculosis Challenge in Rhesus Macaques
by Andrew D. White, Charlotte Sarfas, Laura S. Sibley, Jennie Gullick, Simon Clark, Emma Rayner, Fergus Gleeson, Martí Català, Isabel Nogueira, Pere-Joan Cardona, Cristina Vilaplana, Mike J. Dennis, Ann Williams and Sally A. Sharpe
Pharmaceutics 2020, 12(5), 394; https://doi.org/10.3390/pharmaceutics12050394 - 25 Apr 2020
Cited by 19 | Viewed by 3779
Abstract
Ten million cases of tuberculosis (TB) were reported in 2018 with a further 1.5 million deaths attributed to the disease. Improved vaccination strategies are urgently required to tackle the ongoing global TB epidemic. In the absence of a validated correlate of protection, highly [...] Read more.
Ten million cases of tuberculosis (TB) were reported in 2018 with a further 1.5 million deaths attributed to the disease. Improved vaccination strategies are urgently required to tackle the ongoing global TB epidemic. In the absence of a validated correlate of protection, highly characterised pre-clinical models are required to assess the protective efficacy of new vaccination strategies. In this study, we demonstrate the application of a rhesus macaque ultra-low dose (ULD) aerosol M. tuberculosis challenge model for the evaluation of TB vaccination strategies by directly comparing the immunogenicity and efficacy of intradermal (ID) and aerosol BCG vaccination delivered using a portable vibrating mesh nebulizer (VMN). Aerosol- and ID-delivered Bacille Calmette-Guérin (BCG) induced comparable frequencies of IFN-γ spot forming units (SFU) measured in peripheral blood mononuclear cells (PBMCs) by ELISpot, although the induction of IFN-γ SFU was significantly delayed following aerosol immunisation. This delayed response was also apparent in an array of secreted pro-inflammatory and chemokine markers, as well as in the frequency of antigen-specific cytokine producing CD4 and CD8 T-cells measured by multi-parameter flow cytometry. Interrogation of antigen-specific memory T-cell phenotypes revealed that vaccination-induced CD4 and CD8 T-cell populations primarily occupied the central memory (TCM) and transitional effector memory (TransEM) phenotype, and that the frequency of CD8 TCM and TransEM populations was significantly higher in aerosol BCG-vaccinated animals in the week prior to M. tuberculosis infection. The total and lung pathology measured following M. tuberculosis challenge was significantly lower in vaccinated animals relative to the unvaccinated control group and pathology measured in extra-pulmonary tissues was significantly reduced in aerosol BCG-vaccinated animals, relative to the ID-immunised group. Similarly, significantly fewer viable M. tuberculosis CFU were recovered from the extra-pulmonary tissues of aerosol BCG-vaccinated macaques relative to unvaccinated animals. In this study, a rhesus macaque ULD M. tuberculosis aerosol challenge model was applied as a refined and sensitive system for the evaluation of TB vaccine efficacy and to confirm that aerosol BCG vaccination delivered by portable VMN can confer a significant level of protection that is equivalent, and by some measures superior, to intradermal BCG vaccination. Full article
(This article belongs to the Special Issue Tuberculosis Vaccine Research and Development)
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Review

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25 pages, 312 KiB  
Review
Preclinical Progress of Subunit and Live Attenuated Mycobacterium tuberculosis Vaccines: A Review following the First in Human Efficacy Trial
by Jacqueline Watt and Jun Liu
Pharmaceutics 2020, 12(9), 848; https://doi.org/10.3390/pharmaceutics12090848 - 06 Sep 2020
Cited by 9 | Viewed by 3175
Abstract
Tuberculosis (TB) is the global leading cause of death from an infectious agent with approximately 10 million new cases of TB and 1.45 million deaths in 2018. Bacille Calmette-Guérin (BCG) remains the only approved vaccine for Mycobacterium tuberculosis (M. tb, causative [...] Read more.
Tuberculosis (TB) is the global leading cause of death from an infectious agent with approximately 10 million new cases of TB and 1.45 million deaths in 2018. Bacille Calmette-Guérin (BCG) remains the only approved vaccine for Mycobacterium tuberculosis (M. tb, causative agent of TB), however clinical studies have shown BCG has variable effectiveness ranging from 0–80% in adults. With 1.7 billion people latently infected, it is becoming clear that vaccine regimens aimed at both post-exposure and pre-exposure to M. tb will be crucial to end the TB epidemic. The two main strategies to improve or replace BCG are subunit and live attenuated vaccines. However, following the failure of the MVA85A phase IIb trial in 2013, more varied and innovative approaches are being developed. These include recombinant BCG strains, genetically attenuated M. tb and naturally attenuated mycobacteria strains, novel methods of immunogenic antigen discovery including for hypervirulent M. tb strains, improved antigen recognition and delivery strategies, and broader selection of viral vectors. This article reviews preclinical vaccine work in the last 5 years with focus on those tested against M. tb challenge in relevant animal models. Full article
(This article belongs to the Special Issue Tuberculosis Vaccine Research and Development)
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