title: Increased protective efficacy of recombinant BCG strains expressing virulence-neutral proteins of the ESX-1 secretion system.
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.
  
  
  CONCLUSIONS
  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: 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.
authors: Daria
authors: D
authors: Bottai
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
authors: Wafa
authors: W
authors: Frigui
authors: Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Simon
authors: S
authors: Clark
authors: Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Emma
authors: E
authors: Rayner
authors: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors: Andrea
authors: A
authors: Zelmer
authors: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors: Nuria
authors: N
authors: Andreu
authors: Laboratory of Pediatric Infectious Diseases, Radboud University Medical Center Nijmegen, The Netherlands.
authors: Marien I
authors: MI
authors: de Jonge
authors: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors: Gregory J
authors: GJ
authors: Bancroft
authors: Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors: Ann
authors: A
authors: Williams
authors: Université de Lille, Institut Pasteur de Lille, Inserm U1019, CNRS UMR8204, France.
authors: Priscille
authors: P
authors: Brodin
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France. Electronic address: roland.brosch@pasteur.fr.
authors: Roland
authors: R
authors: Brosch
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis* / Q000235:genetics; D001500:BCG Vaccine / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics; D015169:Colony Count, Microbial; D005260:Female; D006168:Guinea Pigs; D008168:Lung / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D013154:Spleen / Q000382:microbiology; D016019:Survival Analysis; D016896:Treatment Outcome; D014376:Tuberculosis / Q000517:prevention & control*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D014614:Vaccines, Synthetic
keywords: ESAT-6; ESX-1 secretion system; Recombinant BCG; Tuberculosis; Vaccine