Scientists at the Institut Pasteur and their partners in the international TBVAC2020 consortium have just developed a tuberculosis vaccine candidate derived from conventional BCG. This vaccine candidate has higher efficacy, due to a heterologous system of protein secretion that increases the quality and magnitude of the immune responses to virulent strains of Mycobacterium tuberculosis.

These promising results were published in the journal Cell Reports on March 14, 2017.

Scientists at the Institut Pasteur have for several years been able to highlight mechanisms that characterize the interaction of M. tuberculosis with the host's immune cells. During infection the bacterium uses a specialized secretion system known as ESX–1 to compromise the integrity of the vacuole membrane of the host cell in which it is enclosed. Subsequent rupture of this membrane brings the mycobacterial components into contact with the cytosol of host cell. This is the signal for triggering a series of innate immune responses contributing to the control of mycobacterial growth. Due to a deletion of a chromosomal region, BCG lacks the ESX–1 secretion system. Its protective action is therefore not based on this powerful cascade of innate immune responses.

This prompted scientists at the Unit for Integrated Mycobacterial Pathogenomics at the Institut Pasteur, led by Roland Brosch, to explore this new avenue with the aim of developing a more effective vaccine candidate than BCG, based on the concept that restoring these innate immune responses to a vaccine strain may improve immunogenicity. By expressing the ESX–1 secretion system of Mycobacterium marinum, a low–virulence aquatic mycobacterium, they constructed a recombinant BCG strain able to induce the same type of immune response as M. tuberculosis. "The key mechanism is the contact established between the bacterial components and cytosol – which is found inside the host cell. Conventional BCG remains imprisoned in a vacuole and does not communicate to any great extent with the host cell cytosol", explained Roland Brosch. The innate and adaptive immune responses achieved with the new strain are qualitatively and quantitatively enhanced and result in improved recognition of mycobacterial antigens. The virulence of the strain produced in this way is also attenuated, which makes it a promising vaccine candidate. Mice vaccinated with this strain have shown better protection against subsequent infection by M. tuberculosis than mice vaccinated with conventional BCG.

These results were published in the journal Cell Reports, and offer new possibilities for the development of a more effective vaccine against the various pathologies caused by M. tuberculosis, in particular pulmonary tuberculosis in adults. Further experiments are being carried out with a view to future clinical developments, including human trials. "We have filed a patent relating to this strain, with the objective of moving on to clinical trials in the future," Roland Brosch was pleased to announce.