000057727 001__ 57727
000057727 005__ 20210121114501.0
000057727 0247_ $$2doi$$a10.1016/S2213-2600(15)00435-X
000057727 0248_ $$2sideral$$a96847
000057727 037__ $$aART-2015-96847
000057727 041__ $$aeng
000057727 100__ $$aSpertini, Francois
000057727 245__ $$aSafety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial
000057727 260__ $$c2015
000057727 5060_ $$aAccess copy available to the general public$$fUnrestricted
000057727 5203_ $$aBackground 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 x 10(3) colony forming units (CFU) MTBVAC, those in the second cohort received 5 x 10(4) CFU MTBVAC, and those in the third cohort received 5 x 10(5) CFU MTBVAC. In all cohorts, participants assigned to receive BCG were given 5 x 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 gamma release assays (IGRA) of peripheral blood mononuclear cells. This trial is registered with ClinicalTrials.gov, number NCT02013245. Findings 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 (5x10(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. Interpretation 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.
000057727 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000057727 590__ $$a15.328$$b2015
000057727 591__ $$aCRITICAL CARE MEDICINE$$b1 / 33 = 0.03$$c2015$$dQ1$$eT1
000057727 591__ $$aRESPIRATORY SYSTEM$$b1 / 58 = 0.017$$c2015$$dQ1$$eT1
000057727 592__ $$a5.499$$b2015
000057727 593__ $$aPulmonary and Respiratory Medicine$$c2015$$dQ1
000057727 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000057727 700__ $$aAudran, Regine
000057727 700__ $$aChakour, Reza
000057727 700__ $$aKaroui, Olfa
000057727 700__ $$aSteiner-Monard, Viviane
000057727 700__ $$aThierry, Anne-Christine
000057727 700__ $$aMayor, Carole E.
000057727 700__ $$aRettby, Nils
000057727 700__ $$aJaton, Katia
000057727 700__ $$aVallotton, Laure
000057727 700__ $$aLazor-Blanchet, Catherine
000057727 700__ $$aDoce, Juana
000057727 700__ $$aPuentes, Eugenia
000057727 700__ $$0(orcid)0000-0001-8644-120X$$aMarinova, Dessislava$$uUniversidad de Zaragoza
000057727 700__ $$0(orcid)0000-0001-7897-9173$$aAguilo, Nacho$$uUniversidad de Zaragoza
000057727 700__ $$0(orcid)0000-0003-2993-5478$$aMartin, Carlos$$uUniversidad de Zaragoza
000057727 7102_ $$11008$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cÁrea Microbiología
000057727 7102_ $$11008$$2X$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cProy. investigación HQA
000057727 773__ $$g3, 12 (2015), 953-962$$pThe Lancet. Respir. med.$$tThe Lancet. Respiratory medicine$$x2213-2600
000057727 8564_ $$s1721981$$uhttps://zaguan.unizar.es/record/57727/files/texto_completo.pdf$$yPostprint
000057727 8564_ $$s75477$$uhttps://zaguan.unizar.es/record/57727/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000057727 909CO $$ooai:zaguan.unizar.es:57727$$particulos$$pdriver
000057727 951__ $$a2021-01-21-10:51:23
000057727 980__ $$aARTICLE