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 the widespread use of BCG. MTBVAC is a new live tuberculosis vaccine based on a genetically attenuated phoP-/fadD26-deletion mutant of M. tuberculosis that expresses most antigens present in human isolates in contrast to BCG. Methods We conducted this randomized, double-blind, controlled phase I study at CHUV, Lausanne, Switzerland, to compare MTBVAC to BCG in healthy, PPD-negative adults. Primary outcome was safety in all vaccinated participants. Secondary outcome included whole blood cell mediated immune response to live MTBVAC and BCG as well as interferon-gamma release assay (IGRA) on peripheral blood mononuclear cells. Volunteers fulfilling the inclusion criteria were randomly allocated (on a 3:1 basis) in a dose-escalation manner to three cohorts. Each cohort included 9 subjects who were injected with MTBVAC 5x10 3 , 5x10 4 , or 5x10 5 colony forming units (CFU) in 0.1 mL and 3 subjects with BCG (single dose of 5x10 5 CFU in 0.1 mL). Each subject received a single intradermal injection in the non-dominant arm starting with the lowest MTBVAC dose. Findings Thirty-six volunteers were recruited. Vaccination with MTBVAC (5x10 3 , 5x10 4 , 5x10 5 CFU/0.1mL) was as safe as with BCG, and did not induce serious adverse events. All individuals were IGRA negative at the end of follow-up (D210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was immunogenic in a dosedependent manner. At the same dose level as BCG (5x10 5 CFU), although no

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

“…2.5×10 7 CFU. By this route and dose of administration, all data showed comparable safety and attenuation profile for MTBVAC (and SO2) and BCG SSI, which is the strain used as control comparator in MTBVAC phase I clinical evaluation in adults [70] and in newborns (NCT02013245). Additionally, biodistribution and formal toxicity studies showed that intradermal inoculation of MTBVAC presents lack of toxicity, limited organ biodistribution and persistence, and untraceable excretion in urine and stool up to six months post vaccination, comparable to BCG SSI, as well as appears to be less reactogenic than BCG in mice and guinea pigs [39].…”

“…This calls for significant considerations for the potential implications of the current Quantiferon assay for in vitro diagnosis of TB infection (based on ESAT-6, CFP-10 and TB7.7) in MTBVAC clinical trials in TBendemic regions. Relevant to this, in the MTBVAC phase Ia trial in adults in Lausanne, ELISpot conversion data to PPD, and to separate antigens ESAT-6 and CFP-10 showed responses to ESAT-6 that stayed below threshold for a positive test readout of infection with M. tuberculosis, while there was a transient increase in CFP-10-specific IFNγ response over the limit of positivity in two of nine subjects from the intermediate MTBVAC dose group (5×10 4 CFU) and in one subject of MTBVAC high-dose group (5x10 5 CFU) at day 28, which at day 270 (end of study) was below threshold for M. tuberculosis infection [70]. These results are supported by recent data in goats where vaccination with SO2 induced a transient ESAT-6/ CFP-10 positivity in 50% of the animals [82].…”

“…The study primary objective was safety and local tolerance of MTBVAC in comparison with BCG SSI with minimum secondary immunogenicity in healthy adult volunteers without any history of BCG vaccination, or exposure to TB (PPD-negative) and or HIV. Successful completion demonstrated that vaccination with MTBVAC was at least as safe as BCG, and did not induce serious adverse events [70]. And although no statistical significance could be achieved due to the small group size of the trial, the immunogenicity data showed that MTBVAC was at least as immunogenic as BCG, and at the same dose level as BCG, MTBVAC group showed greater frequency of polyfunctional CD4 + central memory T cells.…”

“…Moreover, the MTBVAC project has counted with a robust preclinical, regulatory and clinical expertise from the TBVI Product Development and Clinical Development Teams (TBVI PDT and CDT), gratefully acknowledged in [39] and [70]. In Oct 2012, MTBVAC was granted approval to enter a first-inhuman phase Ia clinical trial at Lausanne University Hospital (CHUV) in Switzerland, led by the Principal Investigator (PI) Prof. François Spertini.…”

“…to BCG vaccination at birth), exact clinical route, and regimen of vaccination, and the clinical immunological assays used or planned for use for vaccine characterization and dose definition. For example, the whole-blood intracellular staining (WB-ICS) assay, originally developed by Prof. Willem Hanekom (former SATVI director, current deputy director TB vaccines at BMGF) is now widely used as one of the standard immunological characterization tests in TB vaccine clinical trials, as in the phase Ia of MTBVAC [70] or in other trials at SATVI [37,[93][94][95][96]. Moreover, considerations for investigating ESAT-6 and CFP-10 conversion kinetics and how they can relate to vaccine induced protection will be made.…”