Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree.

The original Mycobacterium bovis Bacillus Calmette Guérin vaccine strain has developed into several different substrains which have been used for production of BCG vaccines throughout the world since 1921. Based on the latest genetic and antigenic knowledge, as well as the early literature reports on BCG vaccination, we are able to fit the different pieces of the BCG puzzle together and outline the origin of the different substrains of M. bovis BCG. The BCG vaccine substrains analysed demonstrate two distinct patterns, with an abrupt change consisting of a loss of several genes and altered biochemical characteristics in strains originating from Institut Pasteur after 1927. Further evidence from the literature is provided that a change occurred in virulence of the BCG parent strain at Institut Pasteur in the late 1920s. Based on this information a genealogical tree is proposed and discussed.