Development of new vaccines and drugs for TB: limitations and potential strategic errors

Abstract

The concomitant HIV and TB epidemics pose an enormous threat to humanity. After invading the host Mycobacterium tuberculosis initially behaves as an intracellular pathogen, which elicits the emergence of acquired specific resistance in the form of a T-helper-1 T-cell response, and involves the secretion of a myriad of cytokines and chemokines to drive protective immunity and granuloma formation. However, after that, a second phase of the disease process involves survival of bacilli in an extracellular state that is still poorly understood. This article briefly reviews the various strategies currently being used to improve both vaccination and drug therapy of TB, and attempts to make the argument that current viewpoints that dominate [both the field and the current literature] may be seriously flawed. This includes both the choice of new vaccine and drug candidates, and also the ways these are being tested in animal models, which in the opinion of the author run the risk of driving the field backwards rather than forward.

Figure 1. Primary granulomas in the infected guinea pig lung

(A) Typical primary lung lesion appearance at day 60 in the guinea pig. There is a large region of central necrosis that is undergoing dystrophic calcification, surrounded by a ribbon or rim of eosinophilic acellular debris. (B) A lung lesion visualized by combination staining with auramine O and rhodamine B to detect acid fast bacteria, hematoxylin QS (tissue stain), and 4’6-diamidino-2-phenylindole dihydrochloride (nuclear stain). There are multiple single bacterial cells and small clusters of bacteria scattered throughout the central necrosis and acellular rim. (A) Colorado State University, CO, USA. (B) Courtesy of Anne Lenaerts and Gavin Ryan, Colorado State University, CO, USA.