Variable Virulence and Efficacy of BCG Vaccine Strains in Mice and Correlation With Genome Polymorphisms

Abstract

Bacille Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. However, BCG is not an ideal vaccine and has two major limitations: BCG exhibits highly variable effectiveness against the development of TB both in pediatric and adult populations and can cause disseminated BCG disease in immunocompromised individuals. BCG comprises a number of substrains that are genetically distinct. Whether and how these genetic differences affect BCG efficacy remains largely unknown. In this study, we performed comparative analyses of the virulence and efficacy of 13 BCG strains, representing different genetic lineages, in SCID and BALB/c mice. Our results show that BCG strains of the DU2 group IV (BCG-Phipps, BCG-Frappier, BCG-Pasteur, and BCG-Tice) exhibit the highest levels of virulence, and BCG strains of the DU2 group II (BCG-Sweden, BCG-Birkhaug) are among the least virulent group. These distinct levels of virulence may be explained by strain-specific duplications and deletions of genomic DNA. There appears to be a general trend that more virulent BCG strains are also more effective in protection against Mycobacterium tuberculosis challenge. Our findings have important implications for current BCG vaccine programs and for future TB vaccine development.

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

“…The majority (82%) of these absent epitopes are contained in 6 antigenic proteins encoded in RD1 and RD2 deleted in BCG strains. These and related studies further suggested that epitope sequence variation in BCG potentially affects human T cell recognition that could result in ineffective priming of the host immune system [16,17,[50][51][52].…”

“…It is thought that over-attenuation of BCG due to loss of important immunodominant antigens (e.g. those in the region of difference 1 (RD1) region) in the process of its attenuation by repeated subcultivation passaging in nonstandardized conditions could be one of the reasons [16,17]. Moreover, large number of human clinical trials suggest that revaccination with BCG does not provide additional benefit, which could be due to preexisting heterologous immunity resulting from infection with nontuberculous environmental mycobacteria (NTM), a process known as masking and blocking [18,19].…”

Assessment of recombinant plasmid expressing fusion antigen Ag85B-Rv3425 in management of acute tuberculosis infection in mice

“…Unfortunately, BCG (bacillus Calmette-Guérin), the only vaccine widely used against TB, provides varied protective efficacy (0-80% in randomized control trials) (3)(4)(5). Recently, the emergence of drug-resistant Mtb stains as well as HIV-TB co-infection poses numerous complexities for TB control (6,7).…”

Effect of a low dose of BCG-Phipps vaccine on the development of reactivity to tuberculin skin test in neonatal calves and adult cows

“…In a study realized by Zhang et al (2016) assessing the virulence and efficacy of 13 BCG strains in SCID and BALB/c, showed that BCG strains of the DU2 group IV to which BCG-Phipps belongs, showed the highest levels of virulence among strains studied. They reported that these distinct levels of virulence could be explained by strainspecific duplications and deletions of genomic DNA.…”