Introduction Tuberculosis remains a significant global disease burden with an estimated 9 million new cases and 1.5 million deaths in 2013. BCG continues to be the only licensed TB vaccine, however it is poorly efficacious against adult pulmonary TB disease and there is a desperate need for a better vaccine to provide greater and more consistent protection. Development of such a vaccine has been hampered by the lack of reliable and validated correlates of protection. A human mycobacterial challenge model, using BCG as a surrogate for Mycobacterium tuberculosis challenge would facilitate improved vaccine selection for progression into future field efficacy testing. In this study we evaluate the effect of two BCG strains at two doses to optimise this model.
Methods 40 healthy BCG-naïve adults were assigned to one of four groups to receive intradermal BCG SSI or BCG Tice at standard or high dose. Two weeks following BCG challenge, skin biopsy from the BCG challenge site was performed. Volunteers were followed up for 28 days from challenge to assess reactogenicity and ensure no safety concerns. BCG mycobacterial load was quantified by solid culture and quantitative PCR.
Results BCG, regardless of strain or dose, was tolerated well and reactogenicity was similar between groups. BCG strain did not significantly affect BCG recovery from skin biopsy, however there was significantly greater recovery from the high dose challenge groups compared with the standard dose. Consistent with previous findings there was an inverse correlation between ex-vivo IFN-γ ELISpot responses to PPD and amount of BCG recovered from the skin biopsies.
Conclusions High dose BCG challenge regardless of strain used, significantly improves the sensitivity of this human mycobacterial challenge model. Practical reasons favour the use of BCG SSI over BCG Tice, as BCG SSI is licensed for intradermal administration in the UK and preparation is more straightforward with less product wastage or variability in dose between vials of BCG SSI. Looking ahead we plan to use this optimised BCG SSI challenge model to evaluate novel TB vaccine candidates in order to improve the selection of which vaccines then progress to expensive field efficacy trials.