Microevolution of BCG substrains.

Tuberculosis was, and still is, one of the main causes of morbidity and mortality in the world. Thus it still remains a public health priority. Nonetheless, without a newly developed vaccine, it is rather unlikely to be easily resolved. The only available vaccine against tuberculosis (BCG) has been used for nearly 100 years. Currently a variety of BCG substrains are used by many manufacturers in the world. All these substrains were obtained from a single parental strain of Mycobacterium bovis. Attempts to explain the complete mechanisms of attenuation, as well as tracing the microevolution resulting from the different distribution time and conditions of production of BCG vaccines in the different parts of the world, might explain the differences in the observed efficacy of vaccines produced with different substrains. The most important marker associated with attenuation of virulent M. bovis is the loss of the RD1 region observed in all BCG substrains. Among other attenuation markers, still not completely identified, accumulation of SNP mutations seems to be an important one. The different number of passages and culture conditions of the parental vaccine strain have led to there being about 50 different sister vaccine BCG substrains throughout the world. Among them, there are "early strains", distributed until 1927, and "later strains" with the RD2 deletion obtained during 1927‑1961. It has also been found that 22 regions containing 52 genes were lost during the distribution of sister substrains during the period 1924‑1966. Genetic differences due to selection pressure, revealing specific microevolutionary traits, may explain the variability in immunogenicity and residual virulence of each vaccine BCG substrain.