Abstract
To date, most new vaccines against Mycobacterium tuberculosis, including new recombinant versions of the current BCG vaccine, have usually been screened against the laboratory strains H37Rv or Erdman. In this study we took advantage of our recent work in characterizing an increasingly large panel of newly emerging clinical isolates [from the United States or from the Western Cape region of South Africa], to determine to what extent vaccines would protect against these [mostly high virulence] strains. We show here that both BCG Pasteur and recombinant BCG Aeras-422 [used here as a good example of the new generation BCG vaccines] protected well in both mouse and guinea pig low dose aerosol infection models against the majority of clinical isolates tested. However, Aeras-422 was not effective in a long term survival assay compared to BCG Pasteur. Protection was very strongly expressed against all of the Western Cape strains tested, reinforcing our viewpoint that any attempt at boosting BCG would be very difficult to achieve statistically. This observation is discussed in the context of the growing argument made by others that the failure of a recent vaccine trial disqualifies the further use of animal models to predict vaccine efficacy. This viewpoint is in our opinion completely erroneous, and that it is the fitness of prevalent strains in the trial site area that is the centrally important factor, an issue that is not being addressed by the field.
Highlights
Tuberculosis remains a global emergency, with ~9-million new cases occurring each year, and 1.5-million deaths [1]
In the current study we addressed the question of whether BCG is effective against newly emerging clinical strains of M.tuberculosis in mouse and guinea pig models—the two most widely used animal screens
These results indicate that BCG can give rise to a range of protective efficacy against different clinical isolates. This is not directly related to virulence, since all the isolates used here grew well in the animal models, but instead seems to point to bacterial fitness as a major factor. If, as these results suggest, Western Cape strains are generally of low fitness [spreading as they do in a region where malnutrition and high rates of HIV are major factors] and as a result are highly inhibited by prior BCG vaccination as shown below, it would be very difficult if not impossible to demonstrate in these models any positive effects of boosting regimens
Summary
Tuberculosis remains a global emergency, with ~9-million new cases occurring each year, and 1.5-million deaths [1]. The incidence of new infections that are drug-resistant is estimated at nearly half a million cases [2], leading increasingly to poor treatment outcomes and increases in mortality. Much of the current epidemic is driven by the concomitant HIV epidemic [3], in Southern Africa, and other risks factors are emerging, including diabetes [4,5]. Considerable effort is being made to try to develop new vaccines and drugs to combat the tuberculosis epidemic.
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