No abstract

The establishment of an aerosol challenge model in nonhuman primates (NHPs) for the testing of vaccines against Mycobacterium tuberculosis would assist the global effort to optimize novel vaccination strategies. The endpoints used in preclinical challenge studies to identify measures of disease burden need to be accurate and sensitive enough to distinguish subtle differences and benefits afforded by different tuberculosis (TB) vaccine regimens when group sizes are inevitably small. This study sought to assess clinical and nonclinical endpoints as potentially sensitive measures of disease burden in a challenge study with rhesus macaques by using a new protocol of aerosol administration of M. tuberculosis. Immunological and clinical readouts were assessed for utility in vaccine evaluation studies. This is the first example of TB vaccine evaluation with rhesus macaques where long-term survival was one of the primary endpoints. However, we found that in NHP vaccine efficacy studies with maximum group sizes of six animals, survival did not provide a valuable endpoint. Two approaches used in human clinical trials for the evaluation of the gamma interferon (IFN-␥) response to vaccination (enzyme-linked immunospot [ELISpot] assay and enzyme-linked immunosorbent assay [ELISA])were included in this study. The IFN-␥ profiles induced following vaccination were found not to correlate with protection, nor did the level of purified protein derivative (PPD)-specific proliferation. The only readout to reliably distinguish vaccinated and unvaccinated NHPs was the determination of lung lesion burden using magnetic resonance (MR) imaging combined with stereology at the end of the study. Therefore, the currently proposed key markers were not shown to correlate with protection, and only imaging offered a potentially reliable correlate.Tuberculosis (TB) is a reemerging infectious disease and is responsible for nearly 2 million deaths and 9 million new cases each year (36). The global TB pandemic has been exacerbated by the emergence of drug-resistant strains of Mycobacterium tuberculosis, which render treatment less effective, and by the HIV epidemic, where coinfection with HIV greatly increases the risk of reactivation of latent TB and susceptibility to active TB disease.The most effective means of controlling this global epidemic would be by prophylactic immunization. Mycobacterium bovis bacille Calmette-Guérin (BCG), the only licensed TB vaccine, is administered to neonates in high-risk populations as part of the WHO Expanded Programme on Immunization. BCG consistently protects against TB meningitis and disseminated TB in childhood (27,30), but its efficacy wanes with time, and it affords only variable protection against pulmonary disease (10). A new, more effective TB vaccine is a major global health priority and is an important part of the WHO STOP TB partnership strategy.A large international effort is under way to develop a more effective vaccine. The leading TB vaccine development strategy involves vaccination with BCG followe...