Tuberculosis (TB) remains a global health burden for which safe vaccines are needed. BCG has limitations as a TB vaccine so we have focused on live attenuated Mycobacterium tuberculosis mutants as vaccine candidates. Prior to human studies, however, it is necessary to demonstrate safety in non-human primates (NHP). In this study, we evaluate the safety and efficacy of two live attenuated M. tuberculosis double deletion vaccine strains mc26020 (ΔlysA ΔpanCD) and mc26030 (ΔRD1 ΔpanCD) in cynomolgus macaques. In murine models, mc26020 is rapidly cleared while mc26030 persists. Both mc26020 and mc26030 were safe and well tolerated in cynomolgus macaques. Following a high-dose intrabronchial challenge with virulent M. tuberculosis, mc26020-vaccinates were afforded a level of protection intermediate between that elicited by BCG vaccination and no vaccination. BCG vaccinates had reduced tuberculosis-associated pathology and improved clinical scores as compared to saline and mc26030 vaccinates, but survival did not differ among the groups.
Although genetic factors may affect susceptibility to tuberculosis, studies that have assessed variants of the natural resistance-associated macrophage protein 1 gene (NRAMP1) and their association with tuberculosis in humans have yielded conflicting results. It is likely that NRAMP1 polymorphisms may be associated with progression to severe forms of pulmonary tuberculosis rather than with susceptibility to Mycobacterium tuberculosis infection. To test this possibility, we examined NRAMP1 variants at the INT4 and D543N loci, as well as their association with severe forms of pulmonary tuberculosis, in 127 patients with active pulmonary tuberculosis and in 91 ethnically matched, healthy control subjects in areas of China where tuberculosis is endemic. We found that NRAMP1 polymorphisms at these 2 loci were significantly associated with 2 severe forms of pulmonary tuberculosis: sputum smear-positive tuberculosis and cavitary tuberculosis. The NRAMP1 variants were not associated with pulmonary M. tuberculosis infection, when analyses of all patients with tuberculosis and all control subjects were performed. The findings of the present study support the hypothesis that genetic variants of NRAMP1 may have an effect on bacilli growth and on outcomes of pulmonary tuberculosis, but not on susceptibility to M. tuberculosis infection.
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