Daria Bottai1, Wafa Frigui2, Simon Clark3, Emma Rayner3, Andrea Zelmer4, Nuria Andreu4, Marien I de Jonge5, Gregory J Bancroft4, Ann Williams3, Priscille Brodin6, Roland Brosch7. 1. Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France; Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, University of Pisa, Pisa, Italy. Electronic address: daria.bottai@unipi.it. 2. Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France. 3. Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom. 4. London School of Hygiene and Tropical Medicine, London, United Kingdom. 5. Laboratory of Pediatric Infectious Diseases, Radboud University Medical Center Nijmegen, The Netherlands. 6. Université de Lille, Institut Pasteur de Lille, Inserm U1019, CNRS UMR8204, France. 7. Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France. Electronic address: roland.brosch@pasteur.fr.
Abstract
BACKGROUND: Mycobacterium bovis BCG is presently the only available anti-tuberculosis vaccine used, worldwide. While BCG protects against miliary tuberculosis (TB) and tuberculoid meningitis in children, it often fails to protect against adult pulmonary TB. It is thus imperative that new improved anti-TB vaccines are developed. The integration of the ESX-1 secretion system, absent from BCG due to the deletion of region of difference 1 (RD1), into the genome of BCG has been shown to confer to BCG::ESX-1 enhanced protection against TB as compared to BCG. METHODS: In the present study, to counterbalance the increase in virulence resulting from the integration of the RD1 region into BCG, we have constructed and evaluated several BCG::ESX-1 variants that carry selected amino-acid changes in the ESX-1-secreted antigen ESAT-6. In order to find the candidate that combines low virulence with high protective efficacy, these novel recombinant BCG::ESX-1 strains were tested for their virulence properties and their protective efficacy against Mycobacterium tuberculosis in two different animal models (mouse and guinea-pig). RESULTS: Among several candidates tested, the BCG::ESAT-L28A/L29S strain, carrying modifications at residues Leu(28)-Leu(29) of the ESAT molecule, showed strong attenuation in mice and high protective efficiency both in mouse and guinea-pig vaccination-infection models. CONCLUSION: This strain thus represents a promising candidate that merits further investigations and development. Our research also provides the proof of concept that selected ESX-1-complemented BCG strains may show low virulence and increased protective potential over parental strains.
BACKGROUND:Mycobacterium bovis BCG is presently the only available anti-tuberculosis vaccine used, worldwide. While BCG protects against miliary tuberculosis (TB) and tuberculoid meningitis in children, it often fails to protect against adult pulmonary TB. It is thus imperative that new improved anti-TB vaccines are developed. The integration of the ESX-1 secretion system, absent from BCG due to the deletion of region of difference 1 (RD1), into the genome of BCG has been shown to confer to BCG::ESX-1 enhanced protection against TB as compared to BCG. METHODS: In the present study, to counterbalance the increase in virulence resulting from the integration of the RD1 region into BCG, we have constructed and evaluated several BCG::ESX-1 variants that carry selected amino-acid changes in the ESX-1-secreted antigen ESAT-6. In order to find the candidate that combines low virulence with high protective efficacy, these novel recombinant BCG::ESX-1 strains were tested for their virulence properties and their protective efficacy against Mycobacterium tuberculosis in two different animal models (mouse and guinea-pig). RESULTS: Among several candidates tested, the BCG::ESAT-L28A/L29S strain, carrying modifications at residues Leu(28)-Leu(29) of the ESAT molecule, showed strong attenuation in mice and high protective efficiency both in mouse and guinea-pigvaccination-infection models. CONCLUSION: This strain thus represents a promising candidate that merits further investigations and development. Our research also provides the proof of concept that selected ESX-1-complemented BCG strains may show low virulence and increased protective potential over parental strains.
Authors: Sangeeta Tiwari; Taru S Dutt; Bing Chen; Mei Chen; John Kim; Annie Zhi Dai; Regy Lukose; Crystal Shanley; Amy Fox; Burton R Karger; Steven A Porcelli; John Chan; Brendan K Podell; Andres Obregon-Henao; Ian M Orme; William R Jacobs; Marcela Henao-Tamayo Journal: Vaccine Date: 2020-09-23 Impact factor: 3.641
Authors: Andreas Kupz; Ulrike Zedler; Manuela Stäber; Carolina Perdomo; Anca Dorhoi; Roland Brosch; Stefan H E Kaufmann Journal: J Clin Invest Date: 2016-04-25 Impact factor: 14.808
Authors: Fabien Le Chevalier; Alessandro Cascioferro; Wafa Frigui; Alexandre Pawlik; Eva C Boritsch; Daria Bottai; Laleh Majlessi; Jean Louis Herrmann; Roland Brosch Journal: Sci Rep Date: 2015-11-25 Impact factor: 4.379