Bactericidal Activity in Whole Blood as a Potential Surrogate Marker of Immunity after Vaccination against Tuberculosis

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Abstract
The development of new tuberculosis (TB) vaccines will require the identification of correlates of human protection. This study examined the balance between immunity and virulence in a whole blood infection model in which intracellular mycobacterial survival was measured using BACTEC. In the blood of tuberculin-negative donors, counts ofMycobacterium tuberculosisH37Ra organisms fell by 0.14 log10CFU during 96 h of whole blood culture, whereas counts ofMycobacterium bovisBCG,M. tuberculosisH37Rv, and a clinical TB isolate's organisms increased by 0.13, 0.43, and 1.04 log10CFU, respectively (P< 0.001), consistent with their relative virulence. Inhibition of tumor necrosis factor alpha by the addition of methylprednisolone or pentoxifylline or removal of CD4+or CD8+T cells by magnetic beads had deleterious effects on immune control of intracellular growth only in the blood of tuberculin-positive donors. Repeated vaccination of eight tuberculin-negative volunteers withM. bovisBCG resulted in a 0.3 log (50%) reduction in BCG CFU counts in the model compared to baseline values (P< 0.05). Three of the volunteers responded only after the second vaccination. These experiments indicate that whole blood culture may be used to measure immunity toM. tuberculosisand that further studies of repeated BCG vaccination are warranted.