MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

Marinova, Dessislava; Gonzalo-Asensio, Jesús; Aguilo, Nacho; Martín, Carlos

doi:10.1080/14760584.2017.1324303

Cited by 42 publications

(29 citation statements)

References 86 publications

(158 reference statements)

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“…MTBVAC attenuation is based on two independent stable genetic deletions, without antibiotic resistance markers, introduced into phoP and fadD26 , affecting the production and secretion of selected lipidic and proteic virulence factors of Mtb . MTBVAC presents promising features in preclinical animal models and is presently being evaluated in a phase I clinical trial in newborns in South Africa ( Marinova et al, 2017 ). Other attenuated Mtb strain, presently in preclinical development with promising results in murine infection models, is the Mtb Δppe25-pe19 strain, in which selected PE and PPE proteins of the ESX-5 secretion system have been deleted, but which retains an intact ESX-1 secretion system ( Bottai et al, 2012 ; Sayes et al, 2012 , 2016 ).…”

Section: Perspectivesmentioning

confidence: 99%

The Macrophage: A Disputed Fortress in the Battle against Mycobacterium tuberculosis

2017

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Mycobacterium tuberculosis (Mtb), the etiological agent of human tuberculosis (TB), has plagued humans for thousands of years. TB still remains a major public health problem in our era, causing more than 4,400 deaths worldwide every day and killing more people than HIV. After inhaling Mtb-contaminated aerosols, TB primo-infection starts in the terminal lung airways, where Mtb is taken up by alveolar macrophages. Although macrophages are known as professional killers for pathogens, Mtb has adopted remarkable strategies to circumvent host defenses, building suitable conditions to survive and proliferate. Within macrophages, Mtb initially resides inside phagosomes, where its survival mostly depends on its ability to take control of phagosomal processing, through inhibition of phagolysosome biogenesis and acidification processes, and by progressively getting access to the cytosol. Bacterial access to the cytosolic space is determinant for specific immune responses and cell death programs, both required for the replication and the dissemination of Mtb. Comprehension of the molecular events governing Mtb survival within macrophages is fundamental for the improvement of vaccine-based and therapeutic strategies in order to help the host to better defend itself in the battle against the fierce invader Mtb. In this mini-review, we discuss recent research exploring how Mtb conquers and transforms the macrophage into a strategic base for its survival and dissemination as well as the associated defense strategies mounted by host.

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Section: Perspectivesmentioning

confidence: 99%

The Macrophage: A Disputed Fortress in the Battle against Mycobacterium tuberculosis

2017

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“…During the in vitro subcultivation process of BCG attenuation between 1908 and 1921, more than 100 genes were lost from BCG, relative to M. tuberculosis ( 28 ). Deletion of the region of difference 1 (RD1) region, which encodes the protein secretion system ESX-1, is considered the deletion responsible for BCG attenuation ( 28 ) (Figure 1 ).…”

Section: Esat6: a Double-edged Swordmentioning

confidence: 99%

MTBVAC: Attenuating the Human Pathogen of Tuberculosis (TB) Toward a Promising Vaccine against the TB Epidemic

et al. 2017

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Bacille Calmette-Guérin (BCG) is a live-attenuated strain of Mycobacterium bovis developed a century ago by repeated subculture. It remains the only vaccine against tuberculosis (TB) in use today, and it offers variable protection against the respiratory forms of TB responsible for transmission. The principal genetic basis for BCG attenuation is the loss of the region of difference 1 (RD1) that includes the genes codifying for production and export of the major virulence factor ESAT6. Today more than 13 TB vaccine candidates are in clinical evaluation. One of these candidates is MTBVAC, which is based on a rationally attenuated Mycobacterium tuberculosis clinical isolate belonging to modern lineage 4, one of the most widespread lineages among humans. MTBVAC conserves most of the T cell epitopes described for TB including the major immunodominant antigens ESAT6 and CFP10 of the RD1, deleted in BCG. After almost 20 years of discovery and preclinical development, MTBVAC is the only live attenuated vaccine based on a human pathogen that has successfully entered clinical trials as a preventive vaccine in newborns, aiming to replace BCG, and as a preventive vaccine in adolescents and adults (BCG-vaccinated at birth). Our recent preclinical studies have demonstrated that MTBVAC-induced immunity to ESAT6 and CFP10 correlate with improved efficacy relative to BCG encouraging exploration of these responses in human clinical trials as potential biomarkers and identification of these antigens as possible correlates of vaccine-induced protection. Such data would be extremely valuable as they would greatly accelerate clinical development to efficacy trials.

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“…Subunit vaccines contain Mtb antigens expressed as recombinant proteins that are formulated with different adjuvants or expressed by recombinant viral vectors that are used as vehicles for the administration of antigens [47]. Most of the current subunit vaccine candidates are vaccines with limited antigen diversity which are designed to enhance prior immunity mediated by T cells [49] (Figure 3).…”

Section: Tb Vaccine Candidates In Clinical Trialsmentioning

confidence: 99%

Update on TB Vaccine Pipeline

et al. 2020

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In addition to antibiotics, vaccination is considered among the most efficacious methods in the control and the potential eradication of infectious diseases. New safe and effective vaccines against tuberculosis (TB) could be a very important tool and are called to play a significant role in the fight against TB resistant to antimicrobials. Despite the extended use of the current TB vaccine Bacillus Calmette-Guérin (BCG), TB continues to be transmitted actively and continues to be one of the 10 most important causes of death in the world. In the last 20 years, different TB vaccines have entered clinical trials. In this paper, we review the current use of BCG and the diversity of vaccines in clinical trials and their possible indications. New TB vaccines capable of protecting against respiratory forms of the disease caused by sensitive or resistant Mycobacterium tuberculosis strains would be extremely useful tools helping to prevent the emergence of multi-drug resistance.

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MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

Cited by 42 publications

References 86 publications

The Macrophage: A Disputed Fortress in the Battle against Mycobacterium tuberculosis

The Macrophage: A Disputed Fortress in the Battle against Mycobacterium tuberculosis

MTBVAC: Attenuating the Human Pathogen of Tuberculosis (TB) Toward a Promising Vaccine against the TB Epidemic

Update on TB Vaccine Pipeline

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