Abstract
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.
Highlights
The current tuberculosis (TB) vaccine, Bacille Calmette-Guérin (BCG), is an attenuated strain of Mycobacterium bovis based on the etiologic agent of TB in cattle [1]
The main advantage of using rationally attenuated live M. tuberculosis as vaccine is that many genetic regions encoding important immunodominant antigens absent in BCG are still present in attenuated M. tuberculosis, while chromosomal deletions in virulence genes provide assurance for safety and genetic stability (Figure 1)
PhoP has been shown to regulate more than 2% of M. tuberculosis genome, most of which implicated in virulence [17, 18], and this regulation could be mediated through other transcription factors, e.g., Figure 1 | Genomic deletions between human and cattle tuberculosis pathogens
Summary
The current tuberculosis (TB) vaccine, Bacille Calmette-Guérin (BCG), is an attenuated strain of Mycobacterium bovis based on the etiologic agent of TB in cattle [1]. BCG was introduced for the first time into clinical use almost a hundred years ago, when in 1921 it was given orally to an infant whose mother had died of TB a day after delivery. The infant showed no adverse events to vaccination with BCG and importantly, did not develop disseminated TB, the common form of disease at that time acquired mainly form unpasteurized milk of infected cows [2]
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