Optimization of a Human Bacille Calmette-Guérin Challenge Model: A Tool to Evaluate Antimycobacterial Immunity

Background: There is an urgent need for an improved TB vaccine. The lack of a validated correlate of protection slows progress in achieving this goal. A human mycobacterial challenge model, using Bacille Calmette-Guérin (BCG) as a surrogate for a Mycobacterium tuberculosis challenge, would facilitate vaccine selection for field efficacy testing. Optimisation of this model is required. Methods: Healthy BCG-naïve adults were assigned to receive intradermal standard dose BCG SSI (group A), standard dose BCG TICE (group B), high dose BCG SSI (group C) and high dose BCG TICE (group D). Two weeks after BCG challenge, a skin biopsy from the challenge site was performed. BCG mycobacterial load was quantified by solid culture and quantitative polymerase chain reaction. Results: BCG was well tolerated and reactogenicity was similar between groups, regardless of strain and dose. There was significantly greater recovery of BCG from the high dose challenge groups compared to low dose challenge. BCG strain did not significantly affect BCG recovery. Conclusions: BCG challenge dose affects sensitivity of this model. We have selected high dose BCG SSI to take forward in future challenge studies. Assessment of candidate TB vaccine effectiveness with this optimised model could contribute to vaccine selection for efficacy trials.