Divergent effect of bacillus Calmette–Guérin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: Implications for primate models in tuberculosis vaccine research

Abstract

Despite the widespread use of bacillus Calmette-Gué rin vaccination, Mycobacterium tuberculosis infection remains globally the leading cause of death from a single infectious disease. The complicated and often protracted dynamics of infection and disease make clinical trials to test new tuberculosis vaccines extremely complex. Preclinical selection of only the most promising candidates is therefore essential. Because macaque monkeys develop a disease very similar to humans, they have potential to provide important information in addition to small animal models. To assess the relative merits of rhesus and cynomolgus monkeys as screens for tuberculosis vaccines, we compared the efficacy of bacillus Calmette-Gué rin vaccination and the course of infection in both species. Unvaccinated rhesus and cynomolgus monkeys both developed progressive disease with high levels of C-reactive protein, M. tuberculosis-specific IgG, and extensive pathology including cavitation and caseous necrosis. Bacillus Calmette-Gué rin vaccination protected cynomolgus almost completely toward the development of pathology, reflected in a striking 2-log reduction in viable bacteria in the lungs compared with nonvaccinated animals. Rhesus, on the other hand, were not protected efficiently by the bacillus Calmette-Gué rin. The vaccinated animals developed substantial pathology and had negligible reductions of colony-forming units in the lungs. Comparative studies in these closely related species are likely to provide insight into mechanisms involved in protection against tuberculosis.T uberculosis (TB) is the leading global cause of death from a single infectious disease (1, 2), accelerated by the HIV epidemic and appearance of multidrug-resistant Mycobacterium tuberculosis (3). The efficiency of bacillus Calmette-Guérin, the only TB vaccine available for humans, ranges between 0 and 85% (4). Improved vaccines are needed urgently, and a large number of new TB vaccine candidates and delivery systems is being tested in small animal models (5-7). Human trials to evaluate new TB vaccines will be very complex, will often occur in bacillus Calmette-Guérin-immunized populations, will be of long duration, and require large cohorts (8). Effective screens to select only the most promising candidates, delivery systems, and formulations for clinical testing will be extremely valuable. Up to now, almost all efficacy testing of TB vaccine candidates has been in the mouse and͞or guinea pig (9). A more human-like response to TB has been described in the closely related rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques (reviewed in ref. 10). This similarity in response may be because several host molecules implicated in TB infections are present in man and nonhuman primates but are not found, or differ fundamentally, in mice and guinea pigs. For example, many primate species, including human, share the presence of functional Mhc-DR, -DQ, and -DP regions (11). The relevance of this structural similarity is reflected in the observation that spec...

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Confronting the scientific obstacles to global control of tuberculosis

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