Decrease in the Effectiveness of Bacille Calmette-Guérin Vaccine against Pulmonary Tuberculosis: A Consequence of Increased Immune Suppression by Microbial Antioxidants, Not Overattenuation

Clinical Infectious Diseases, Jul 2010

Mutations that arose in bacille Calmette-Guérin (BCG) daughter strains during decades of in vitro cultivation have long been suspected of reducing the efficacy of the BCG vaccine against pulmonary tuberculosis. Although concern was raised 6 decades ago that BCG had become overattenuated, preferential use of relatively virulent BCG vaccines has not restored efficacy. The recent discovery that as BCG evolved its production of antioxidants increased as a consequence of genomic duplications and other mutations suggests the alternative hypothesis that BCG became better at suppressing oxidant-dependent immune responses. This new model of BCG evolution is supported by evidence indicating that reducing BCG antioxidants enhances immunogenicity. Furthermore, some previously unexplained aspects of the performance of the BCG vaccine in clinical trials now make sense in the context of the new model. Finally, the model suggests that the risk of developing pulmonary tuberculosis is influenced by the balance between host-generated oxidants and microbial antioxidants that activate and suppress, respectively, the antigen-presentation pathways that protect the lungs.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://cid.oxfordjournals.org/content/51/2/177.full.pdf

Decrease in the Effectiveness of Bacille Calmette-Guérin Vaccine against Pulmonary Tuberculosis: A Consequence of Increased Immune Suppression by Microbial Antioxidants, Not Overattenuation

Douglas S. Kernodle () 0 0 Departments of Medicine and of Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, Tennessee Mutations that arose in bacille Calmette-Guerin (BCG) daughter strains during decades of in vitro cultivation have long been suspected of reducing the efficacy of the BCG vaccine against pulmonary tuberculosis. Although concern was raised 6 decades ago that BCG had become overattenuated, preferential use of relatively virulent BCG vaccines has not restored efficacy. The recent discovery that as BCG evolved its production of antioxidants increased as a consequence of genomic duplications and other mutations suggests the alternative hypothesis that BCG became better at suppressing oxidant-dependent immune responses. This new model of BCG evolution is supported by evidence indicating that reducing BCG antioxidants enhances immunogenicity. Furthermore, some previously unexplained aspects of the performance of the BCG vaccine in clinical trials now make sense in the context of the new model. Finally, the model suggests that the risk of developing pulmonary tuberculosis is influenced by the balance between host-generated oxidants and microbial antioxidants that activate and suppress, respectively, the antigen-presentation pathways that protect the lungs. - For almost 9 decades, the live vaccine Mycobacterium bovis bacille Calmette-Guerin (BCG) has been used against tuberculosis. In early studies, BCG vaccine was highly efficacious. In the 1920s, vaccination of nursing and medical students with BCG reduced pulmonary tuberculosis by 80% [1]. In the 1930s, a trial in North America found similarly high protection in the first 2 decades after vaccination, with continued benefit for 6 decades [2, 3]. Yet in subsequent studies BCG vaccine exhibited marked variability against pulmonary tuberculosis and occasionally even appeared to increase the risk of developing tuberculosis [4, 5]. This variability is highly significant (P ! .0001) and is regarded as being indicative of true biological differences [4]. Yet despite its flawed record against pulmonary tuberculosis, BCG remains reliably efficacious in preventing tuberculosis meningitis and miliary tuberculosis in young children [6]. Because pulmonary tuberculosis is more common than disseminated tuberculosis, BCG has had a minimal effect on the global burden of tuberculosis, estimated at 9.4 million new active cases and 1.8 million deaths annually [7]. Several hypotheses attempt to explain the variable effectiveness of BCG against pulmonary tuberculosis. These hypotheses include differences between BCG daughter strains (substrains), an inadequate dosage of BCG in some trials, interference by environmental mycobacteria, genetic differences in human populations, and geographic differences in clinical isolates of M. tuberculosis. These hypotheses have been summarized elsewhere [4, 5, 8]. This Viewpoint offers a new perspective on the old idea that the variable efficacy of the BCG vaccine against pulmonary tuberculosis involves differences between BCG daughter strains. In the context of emerging data that reveal that mycobacterial antioxidants suppress host immunity [912] and that antioxidant production increased as BCG evolved [13, 14], the relevant literature is reexamined to reveal an association between BCG daughter strains that produce large amounts of antioxidants and poor efficacy against pulmonary tuberculosis. On the basis of partial but not fully conclusive evidence, a new model is proposed in which BCG, instead of becoming overattenuated, evolved to become better at suppressing the CD8+ T cell responses needed for protection against pulmonary tuberculosis. The new model further suggests that in vitro evolution enabled extensively cultivated BCG substrains to survive longer in vivo, which made them more effective at preventing disseminated tuberculosis. Although overattenuation and increased immune suppression are mutually exclusive models of the evolution of BCG, the new hypothesis is not fully sufficient. Environmental and genetic factors are also crucial, especially in the context of their effect on host oxidant-generating capacity during vaccination. EARLY CONCERN ABOUT OVERATTENUATION AND IDENTIFICATION OF PHENOTYPIC DIFFERENCES AMONG BCG SUBSTRAINS An early theory regarding the apparent decline in efficacy of the BCG vaccine against pulmonary tuberculosis was that the vaccine had changed over time. In 1949, Irvine expressed concern that the problem has now become one of over-attenuation. Separated from its natural habitat for 42 years, may not attenuation still be slowly progressing? [15, p 25]. By the mid1950s, it had been shown that BCG substrains differ in characteristics, including growth rate, their ability to persist in vivo, and their ability to protect mice against M. tuberculosis infection [1619]. Daughter strains are descendents of BCG; before modern technologies for preserving bacteria became (...truncated)


This is a preview of a remote PDF: https://cid.oxfordjournals.org/content/51/2/177.full.pdf

Douglas S. Kernodle. Decrease in the Effectiveness of Bacille Calmette-Guérin Vaccine against Pulmonary Tuberculosis: A Consequence of Increased Immune Suppression by Microbial Antioxidants, Not Overattenuation, Clinical Infectious Diseases, 2010, pp. 177-184, 51/2, DOI: 10.1086/653533