BCG: should clinical trials be reconducted?

The various BCG strains used to vaccinate against tuberculosis throughout the world may not all have the same level of effectiveness. This was the conclusion of a study conducted by researchers from Institut Pasteur, published today in the "Proceedings of the National Academy of Science, USA".

 

 

Press release
Paris, march 12, 2007

 

 

Over three billion individuals have been vaccinated with the Calmette-Guérin bacillus (BCG), an attenuated form of Mycobacterium bovis, the causative agent of bovine type tuberculosis. It should be remembered that BCG is effective in preventing serious forms of tuberculosis in children, but as far as adults are concerned, this protection varies between 0 and 80% depending on the country. It now appears vital for the researchers involved in the fight against tuberculosis to understand the basis of BCG’s protective power and to therefore study the vaccine strains in detail.

The study, conducted by Roland Brosch* and his colleagues from the Bacterial Molecular Genetics Unit at Institut Pasteur, directed by Professor Stewart Cole, in collaboration with the Veterinary Laboratories Agency in Surrey (UK) and the Wellcome Trust Sanger Institute (UK), was aimed at comparing the various strains of BCG currently being used as tuberculosis vaccines.

BCG was developed by the Pasteurians Albert Calmette and Camille Guérin, by the serial passage of a strain of M. bovis, over a period of 13 years on glycerol-soaked potato slices, which caused the bacteria to become less virulent (1921). Once its harmlessness and effectiveness had been established, BCG was then distributed worldwide and maintained by successive cultures in various countries. The researchers have now succeeded in establishing the genealogy of all of these "daughter" strains.

First of all, they obtained the complete genome sequence of the vaccine strain M. bovis BCG Pasteur, which allowed them to gain a better understanding of the attenuation of BCG. They then conducted a comparative study with other BCG strains, which they classified into two groups: the "early" strains, - an ancestral strain developed in the Twenties, some of which, such as the Japanese strain, are still administered today; - and the "late" strains that were distributed more recently (Pasteur, Glaxo, Mérieux, Danish, etc.). The late strains demonstrate more genetic variability than the early strains.

"According to our observations, the early strains of BCG should impart better protection than the late strains", Roland Brosch stressed. "A recently published immunological study has moreover shown better immuno-responsiveness in infants vaccinated with the Japanese strain in comparison with the Danish strain. We feel that it is of the utmost importance that clinical trials are conducted so that the effectiveness of the two vaccine types can be compared".

In 1996, three "late" strains (Danish, Glaxo and Pasteur) represented 66% of the 335 million doses administered worldwide...

The tools developed by the researchers will improve the quality assurance of BCG production, thereby preventing the observed genetic and immunological variabilities. They will also play an instrumental role in the monitoring of "recombinant" BCG strains, BCGs improved by means of genetic engineering methods, which are currently under study at many laboratories throughout the world, including those of the Institut Pasteur.

* Roland Brosch is the 2007 winner of the Georges, Jacques and Elias Canetti prize, which will be awarded on World Tuberculosis Day.

Sources

Genome plasticity of BCG and impact on vaccine efficacity", PNAS on line, March12-16, 2007.
Roland Brosch (1), Stephen V. Gordon (2), Thierry Garnier (1), Karin Eiglmeier (1), Wafa Frigui (1), Philippe Valenti (1), Sandrine Dos Santos (1), Stéphanie Duthoy (1), Céline Lacroix (1), Carmen Garcia-Pelayo (2), Jacqueline K. Inwald (2), Paul Golby (2), Javier Nuñez Garcia (2), R. Glyn Hewinson (2), Marcel A. Behr (3), Michael A. Quail (4), Carol Churcher (4), Bart G. Barell (4), Julian Parkhill (4) and Stewart T. Cole (1)

1. Bacterial Molecular Genetics Unit, Institut Pasteur, Paris, France
2. Veterinary Laboratories Agency, Surrey, United Kingdom
3. McGill University Health Centre, Montréal, Canada
4. The Wellcome Trust Sanger Institute, Cambridge, United Kingdom

Contact persons

Institut Pasteur Press office
Nadine Peyrolo or Corinne Jamma
+33 (0) 1 40 61 33 41
cjamma@pasteur.fr

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