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03 Apr 2017

How to improve BCG vaccine?

Scientists at the Institut Pasteur and collaborators from the international consortium “TBVAC 2020” have just developed a tuberculosis (TB) vaccine candidate. This TB vaccine candidate stemmed from the conventional BCG vaccine (Bacillus Calmette–Guérin vaccine, the only available vaccine against TB) experimentally shows enhanced efficacy. A heterologous proteins secretion system strongly increases the quality and the scale of the immune response against virulent strains of Mycobacterium tuberculosis, the bacterium causing TB. The researchers have published their results in Cell Reports (14 March 2017).

TB is a chronic bacterial infection caused by Mycobacterium tuberculosis. It is still one of the 10 deadliest diseases in the world with 1.8 million people dying from TB each year (WHO) mainly in India, Indonesia, China, Nigeria, Pakistan and South Africa. The BCG vaccine is made from an attenuated Mycobacterium bovis strain. While it is very efficient against the most severe forms of TB in children, it does not sufficiently protect adults, particularly from the most transmissible form: pulmonary TB. Thus, developing a vaccine that would allow a broader protection is a primary objective for TB control.

For several years, scientists at the Institut Pasteur have deciphered the characteristic mechanisms underlying the interaction between Mycobacterium tuberculosis and the host immune cells. During the infection, the bacterium is ingested by host immune cells into their vacuoles. Through the intervention of a specialized secretion system, ESX-1, the locked in bacterium damages the vacuole’s membrane to access the inside of the host cell. This breakout triggers a series of innate immune responses inside the cell to eliminate the bacterium. The BCG strain lacks the ESX-1 secretion system due to the deletion of a chromosome segment. Its protective action does not rely on the trigger of this powerful innate immune chain reaction.

The researchers from the unit “Integrated Mycobacterial Pathogenomics” led by Roland Brosch at the Institut Pasteur in Paris hypothesized that restoring these innate immune responses within a vaccine strain could enhance the immunogenic potential, and in this way improve the BCG vaccine. By expressing the secretion system ESX-1 from Mycobacterium marinum (a low-virulence marine bacterium) in the BCG strain, they created a recombinant BCG strain able to induce the same type of immune response as Mycobacterium tuberculosis. “The key mechanism is setting up a contact between bacterial components and the cytosol of the host cell when the BCG remains trapped by the vacuoles and have limited communication with the host cytosol” said Brosch. The induced innate and adaptive immune responses are both qualitatively and quantitatively improved and allow a better recognition of mycobacterial antigens (mouse vaccination models). The obtained recombinant strain keeps an attenuated virulence property, making it a good vaccine candidate. Mice vaccinated with the new strain were better protected against later infection by highly virulent Mycobacterium tuberculosis compared to mice vaccinated with parental BCG.

© 2017Gröschel et al.

Bosch and his colleagues have published the results in Cell Reports. They have opened up interesting horizons for the development of more efficient vaccine against the different pathologies caused by Mycobacterium tuberculosis, including pulmonary TB in adults. Experiences are in progress prior to a potential clinical development with trials in humans. The scientists have patented their “new BCG strain”.

The paper:

Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection, Cell Reports, Volume 18, Issue 11, p2752–2765, 14 March 2017. http://dx.doi.org/10.1016/j.celrep.2017.02.057

Matthias I. Gröschel (1,2), Fadel Sayes (1), Sung Jae Shin (3), Wafa Frigui (1), Alexandre Pawlik (1), Mickael Orgeur (1), Robin Canetti (1), Nadine Honore (1), Roxane Simeone (1), Tjip S. van der Werf (2), Wilbert Bitter (4, 5), Sang-Nae Cho (3), Laleh Majlessi (1) and Roland Brosch (1, 6)

(1) Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France

(2) Department of Pulmonary Diseases & Tuberculosis, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands

(3) Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 03722 Seoul, South Korea

(4) Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands

(5) Section Molecular Microbiology, Amsterdam Institute of Molecules, Medicine and Systems, Vrije Universiteit Amsterdam,1081 HZ Amsterdam, the Netherlands

(6)   Lead Contact

From Institut Pasteur press release (31 March 2017, in French).