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Frontiers in Immunology 2022Tuberculosis (TB), caused by is the world's deadliest bacterial infection, resulting in more than 1.4 million deaths annually. The emergence of drug-resistance to... (Review)
Review
Tuberculosis (TB), caused by is the world's deadliest bacterial infection, resulting in more than 1.4 million deaths annually. The emergence of drug-resistance to first-line antibiotic therapy poses a threat to successful treatment, and novel therapeutic options are required, particularly for drug-resistant tuberculosis. One modality emerging for TB treatment is therapeutic vaccination. As opposed to preventative vaccination - the aim of which is to prevent getting infected by or developing active tuberculosis, the purpose of therapeutic vaccination is as adjunctive treatment of TB or to prevent relapse following cure. Several candidate therapeutic vaccines, using killed whole-cell or live attenuated mycobacteria, mycobacterial fragments and viral vectored vaccines are in current clinical trials. Other modes of passive immunization, including monoclonal antibodies directed against antigens are in various pre-clinical stages of development. Here, we will discuss these various therapeutics and their proposed mechanisms of action. Although the full clinical utility of therapeutic vaccination for the treatment of tuberculosis is yet to be established, they hold potential as useful adjunct therapies.
Topics: BCG Vaccine; Humans; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis Vaccines; Vaccination
PubMed: 35812462
DOI: 10.3389/fimmu.2022.878471 -
Human Vaccines & Immunotherapeutics Dec 2021Bacillus Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB). However, BCG has variable efficacy and cannot completely prevent TB infection and... (Review)
Review
Bacillus Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB). However, BCG has variable efficacy and cannot completely prevent TB infection and transmission. Therefore, the worldwide prevalence of TB calls for urgent development of a more effective TB vaccine. In the absence of other approved vaccines, it is also necessary to improve the efficacy of BCG itself. Intravenous (IV) BCG administration and BCG revaccination strategies have recently shown promising results for clinical usage. Therefore, it is necessary for us to revisit the BCG vaccination strategies and summarize the current research updates related to BCG vaccination. This literature review provides an updated overview and perspectives of the immunization strategies against TB using BCG, which may inspire the following research on TB vaccine development.
Topics: BCG Vaccine; Humans; Immunization, Secondary; Mycobacterium bovis; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis Vaccines; Vaccination
PubMed: 34856853
DOI: 10.1080/21645515.2021.2007711 -
Nature Reviews. Immunology Feb 2020Novel approaches to vaccine development include structure-based immunogen design, gene-based vaccine platforms and formulation of recombinant antigens with potent... (Review)
Review
Novel approaches to vaccine development include structure-based immunogen design, gene-based vaccine platforms and formulation of recombinant antigens with potent adjuvants. These technologies are producing encouraging results in the development of vaccines for globally important diseases such as tuberculosis, influenza and respiratory syncytial virus. Here we highlight the most important developments in these areas over the past 18 months.
Topics: Adjuvants, Immunologic; BCG Vaccine; Drug Development; Humans; Influenza Vaccines; Influenza, Human; Latent Tuberculosis; RNA, Messenger; Recombinant Proteins; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Tuberculosis Vaccines; Vaccines; Vaccines, Synthetic; Viral Fusion Proteins
PubMed: 31712767
DOI: 10.1038/s41577-019-0243-3 -
Nature Communications Nov 2021Given the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is...
Given the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is support for combining BCG and subunit vaccination for increased efficacy. BCG and Mycobacterium tuberculosis (Mtb) share ~98% of their genome and current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study is to design a TB subunit vaccine composed of antigens not shared with BCG and explore the advantages of this design in a BCG + subunit co-administration vaccine strategy. Eight protective antigens are selected to create an Mtb-specific subunit vaccine, named H107. Whereas traditional vaccines containing BCG-shared antigens exhibit in vivo cross-reactivity to BCG, H107 shows no cross-reactivity and does not inhibit BCG colonization. Instead, co-administering H107 with BCG leads to increased adaptive responses against both H107 and BCG. Importantly, rather than expanding BCG-primed T cells, H107 broadens the overall vaccine repertoire with new T cell clones and introduces 'adjuvant-imprinted' qualities including Th17 responses and less-differentiated Th1 cells. Collectively, these features of H107 are associated with a substantial increase in long-term protection.
Topics: Animals; Antigens, Bacterial; BCG Vaccine; Humans; Immunogenicity, Vaccine; Mice; Mycobacterium bovis; Mycobacterium tuberculosis; Th1 Cells; Th17 Cells; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines, Subunit
PubMed: 34795205
DOI: 10.1038/s41467-021-26934-0 -
The New England Journal of Medicine Jul 2018Recent Mycobacterium tuberculosis infection confers a predisposition to the development of tuberculosis disease, the leading killer among global infectious diseases.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recent Mycobacterium tuberculosis infection confers a predisposition to the development of tuberculosis disease, the leading killer among global infectious diseases. H4:IC31, a candidate subunit vaccine, has shown protection against tuberculosis disease in preclinical models, and observational studies have indicated that primary bacille Calmette-Guérin (BCG) vaccination may offer partial protection against infection.
METHODS
In this phase 2 trial, we randomly assigned 990 adolescents in a high-risk setting who had undergone neonatal BCG vaccination to receive the H4:IC31 vaccine, BCG revaccination, or placebo. All the participants had negative results on testing for M. tuberculosis infection on the QuantiFERON-TB Gold In-tube assay (QFT) and for the human immunodeficiency virus. The primary outcomes were safety and acquisition of M. tuberculosis infection, as defined by initial conversion on QFT that was performed every 6 months during a 2-year period. Secondary outcomes were immunogenicity and sustained QFT conversion to a positive test without reversion to negative status at 3 months and 6 months after conversion. Estimates of vaccine efficacy are based on hazard ratios from Cox regression models and compare each vaccine with placebo.
RESULTS
Both the BCG and H4:IC31 vaccines were immunogenic. QFT conversion occurred in 44 of 308 participants (14.3%) in the H4:IC31 group and in 41 of 312 participants (13.1%) in the BCG group, as compared with 49 of 310 participants (15.8%) in the placebo group; the rate of sustained conversion was 8.1% in the H4:IC31 group and 6.7% in the BCG group, as compared with 11.6% in the placebo group. Neither the H4:IC31 vaccine nor the BCG vaccine prevented initial QFT conversion, with efficacy point estimates of 9.4% (P=0.63) and 20.1% (P=0.29), respectively. However, the BCG vaccine reduced the rate of sustained QFT conversion, with an efficacy of 45.4% (P=0.03); the efficacy of the H4:IC31 vaccine was 30.5% (P=0.16). There were no clinically significant between-group differences in the rates of serious adverse events, although mild-to-moderate injection-site reactions were more common with BCG revaccination.
CONCLUSIONS
In this trial, the rate of sustained QFT conversion, which may reflect sustained M. tuberculosis infection, was reduced by vaccination in a high-transmission setting. This finding may inform clinical development of new vaccine candidates. (Funded by Aeras and others; C-040-404 ClinicalTrials.gov number, NCT02075203 .).
Topics: Adolescent; Antibodies, Bacterial; BCG Vaccine; Child; Female; Humans; Immunization, Secondary; Male; Mycobacterium tuberculosis; Proportional Hazards Models; Seroconversion; Tuberculosis; Tuberculosis Vaccines
PubMed: 29996082
DOI: 10.1056/NEJMoa1714021 -
Seminars in Immunopathology Jun 2020Mycobacterium tuberculosis remains the leading cause of death attributed to a single infectious organism. Bacillus Calmette-Guerin (BCG), the standard vaccine against M.... (Review)
Review
Mycobacterium tuberculosis remains the leading cause of death attributed to a single infectious organism. Bacillus Calmette-Guerin (BCG), the standard vaccine against M. tuberculosis, is thought to prevent only 5% of all vaccine-preventable deaths due to tuberculosis, thus an alternative vaccine is required. One of the principal barriers to vaccine development against M. tuberculosis is the complexity of the immune response to infection, with uncertainty as to what constitutes an immunological correlate of protection. In this paper, we seek to give an overview of the immunology of M. tuberculosis infection, and by doing so, investigate possible targets of vaccine development. This encompasses the innate, adaptive, mucosal and humoral immune systems. Though MVA85A did not improve protection compared with BCG alone in a large-scale clinical trial, the correlates of protection this has revealed, in addition to promising results from candidate such as VPM1002, M72/ASO1E and H56:IC31 point to a brighter future in the field of TB vaccine development.
Topics: BCG Vaccine; Humans; Mycobacterium tuberculosis; Oligodeoxyribonucleotides; Tuberculosis; Tuberculosis Vaccines
PubMed: 32189035
DOI: 10.1007/s00281-020-00794-0 -
Tuberculosis (Edinburgh, Scotland) Dec 2016Tuberculosis (TB) remains a major public health problem internationally, causing 9.6 million new cases and 1.5 million deaths worldwide in 2014. The Bacillus... (Review)
Review
Tuberculosis (TB) remains a major public health problem internationally, causing 9.6 million new cases and 1.5 million deaths worldwide in 2014. The Bacillus Calmette-Guérin vaccine is the only licensed vaccine against TB, but its protective effect does not extend to controlling the development of infectious pulmonary disease in adults. The development of a more effective vaccine against TB is therefore a pressing need for global health. Although it is established that cell-mediated immunity is necessary for the control of latent infection, the presupposition that such immunity is sufficient for vaccine-induced protection has recently been challenged. A greater understanding of protective immunity against TB is required to guide future vaccine strategies against TB. In contrast to cell-mediated immunity, the human antibody response against M.tb is conventionally thought to exert little immune control over the course of infection. Humoral responses are prominent during active TB disease, and have even been postulated to contribute to immunopathology. However, there is evidence to suggest that specific antibodies may limit the dissemination of M.tb, and potentially also play a role in prevention of infection via mucosal immunity. Further, antibodies are now understood to confer protection against a range of intracellular pathogens by modulating immunity via Fc-receptor mediated phagocytosis. In this review, we will explore the evidence that antibody-mediated immunity could be reconsidered in the search for new vaccine strategies against TB.
Topics: Animals; Antibodies, Bacterial; Antibodies, Monoclonal; BCG Vaccine; Humans; Immunity, Cellular; Immunity, Mucosal; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis Vaccines
PubMed: 27865379
DOI: 10.1016/j.tube.2016.08.001 -
Frontiers in Immunology 2018
Topics: BCG Vaccine; History, 20th Century; History, 21st Century; Humans; Mycobacterium tuberculosis; Population Surveillance; Tuberculosis; Tuberculosis Vaccines
PubMed: 29467766
DOI: 10.3389/fimmu.2018.00180 -
Human Vaccines & Immunotherapeutics Aug 2021Despite aggressive eradication efforts, Tuberculosis (TB) remains a global health burden, one that disproportionally affects poorer, less developed nations. The only... (Review)
Review
Despite aggressive eradication efforts, Tuberculosis (TB) remains a global health burden, one that disproportionally affects poorer, less developed nations. The only vaccine approved for TB, the Bacillus of Calmette and Guérin (BCG) vaccine remains controversial because it's stated efficacy has been cited as anywhere from 0 to 80%. Nevertheless, there have been exciting discoveries about the mechanism of action of the BCG vaccine that suggests it has a role in immunization schedules today. We review recent data suggesting the vaccine imparts protection against both tuberculosis and non-tuberculosis pathogens via a newly discovered immune system called trained immunity. BCG's efficacy also appears to be tied to its affect on granulocytes at the epigenetic and hematopoietic stem cell levels, which we discuss in this article at length. We also write about how the different strains of the BCG vaccine elicit different immune responses, suggesting that certain BCG strains are more immunogenic than others. Finally, our review delves into how the current vaccine is being reformulated to be more efficacious, and track the development of the next generation vaccines against TB.
Topics: BCG Vaccine; Humans; Immunization Schedule; Mycobacterium bovis; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis Vaccines
PubMed: 33769193
DOI: 10.1080/21645515.2021.1885280 -
Bulletin of the World Health... May 2023The development of effective tuberculosis vaccines requires significant advances in knowledge and methods and a massive increase in investment. Tatum Anderson reports.
The development of effective tuberculosis vaccines requires significant advances in knowledge and methods and a massive increase in investment. Tatum Anderson reports.
Topics: Humans; Tuberculosis Vaccines; Tuberculosis; Investments; Mycobacterium tuberculosis
PubMed: 37131944
DOI: 10.2471/BLT.23.020523