title: Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial.
abstract: BACKGROUND
  Tuberculosis remains one of the world's deadliest transmissible diseases despite widespread use of the BCG vaccine. MTBVAC is a new live tuberculosis vaccine based on genetically attenuated Mycobacterium tuberculosis that expresses most antigens present in human isolates of M tuberculosis. We aimed to compare the safety of MTBVAC with BCG in healthy adult volunteers.
  
  
  METHODS
  We did this single-centre, randomised, double-blind, controlled phase 1 study at the Centre Hospitalier Universitaire Vaudois (CHUV; Lausanne, Switzerland). Volunteers were eligible for inclusion if they were aged 18-45 years, clinically healthy, HIV-negative and tuberculosis-negative, and had no history of active tuberculosis, chemoprophylaxis for tuberculosis, or BCG vaccination. Volunteers fulfilling the inclusion criteria were randomly assigned to three cohorts in a dose-escalation manner. Randomisation was done centrally by the CHUV Pharmacy and treatments were masked from the study team and volunteers. As participants were recruited within each cohort, they were randomly assigned 3:1 to receive MTBVAC or BCG. Of the participants allocated MTBVAC, those in the first cohort received 5 × 10(3) colony forming units (CFU) MTBVAC, those in the second cohort received 5 × 10(4) CFU MTBVAC, and those in the third cohort received 5 × 10(5) CFU MTBVAC. In all cohorts, participants assigned to receive BCG were given 5 × 10(5) CFU BCG. Each participant received a single intradermal injection of their assigned vaccine in 0·1 mL sterile water in their non-dominant arm. The primary outcome was safety in all vaccinated participants. Secondary outcomes included whole blood cell-mediated immune response to live MTBVAC and BCG, and interferon γ release assays (IGRA) of peripheral blood mononuclear cells. This trial is registered with ClinicalTrials.gov, number NCT02013245.
  
  
  RESULTS
  Between Jan 23, 2013, and Nov 6, 2013, we enrolled 36 volunteers into three cohorts, each of which consisted of nine participants who received MTBVAC and three who received BCG. 34 volunteers completed the trial. The safety of vaccination with MTBVAC at all doses was similar to that of BCG, and vaccination did not induce any serious adverse events. All individuals were IGRA negative at the end of follow-up (day 210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was at least as immunogenic as BCG. At the same dose as BCG (5×10(5) CFU), although no statistical significance could be achieved, there were more responders in the MTBVAC group than in the BCG group, with a greater frequency of polyfunctional CD4+ central memory T cells.
  
  
  CONCLUSIONS
  To our knowledge, MTBVAC is the first live-attenuated M tuberculosis vaccine to reach clinical assessment, showing similar safety to BCG. MTBVAC seemed to be at least as immunogenic as BCG, but the study was not powered to investigate this outcome. Further plans to use more immunogenicity endpoints in a larger number of volunteers (adults and adolescents) are underway, with the aim to thoroughly characterise and potentially distinguish immunogenicity between MTBVAC and BCG in tuberculosis-endemic countries. Combined with an excellent safety profile, these data support advanced clinical development in high-burden tuberculosis endemic countries.
  
  
  BACKGROUND
  Biofabri and Bill & Melinda Gates Foundation through the TuBerculosis Vaccine Initiative (TBVI).
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. Electronic address: Francois.Spertini@chuv.ch.
authors.forename: François
authors.initials: F
authors.lastname: Spertini
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Régine
authors.initials: R
authors.lastname: Audran
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Reza
authors.initials: R
authors.lastname: Chakour
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Olfa
authors.initials: O
authors.lastname: Karoui
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Viviane
authors.initials: V
authors.lastname: Steiner-Monard
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Thierry
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Carole E
authors.initials: CE
authors.lastname: Mayor
authors.affiliation: Vaccination and Immunotherapy Centre, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Nils
authors.initials: N
authors.lastname: Rettby
authors.affiliation: Department of Microbiology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Katia
authors.initials: K
authors.lastname: Jaton
authors.affiliation: Clinical Research Center, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Laure
authors.initials: L
authors.lastname: Vallotton
authors.affiliation: Service de Médecine du Personnel, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lazor-Blanchet
authors.affiliation: Biofabri, Porriño, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Doce
authors.affiliation: Biofabri, Porriño, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Puentes
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Zaragoza, Spain.
authors.forename: Dessislava
authors.initials: D
authors.lastname: Marinova
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Zaragoza, Spain.
authors.forename: Nacho
authors.initials: N
authors.lastname: Aguilo
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Zaragoza, Spain; CIBERES and Research Network on Respiratory Diseases, Spanish Ministry of Health and Instituto de Salud Carlos III, Madrid, Spain; Servicio de Microbiología, Hospital Miguel Servet, ISS Aragón, Zaragoza, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martin
mesh_terms: D000328:Adult; D001500:BCG Vaccine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007114:Immunization; D008297:Male; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000009:adverse effects; D014613:Vaccines, Attenuated
chemical_list: D001500:BCG Vaccine; D032581:Tuberculosis Vaccines; D014613:Vaccines, Attenuated