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

Alice Minhinnick, Stephanie Harris, Morven Wilkie, Jonathan Peter, Lisa Stockdale, Zita-Rose Manjaly-Thomas, Samantha Vermaak, Iman Satti, Paul Moss, Helen McShane, Alice Minhinnick, Stephanie Harris, Morven Wilkie, Jonathan Peter, Lisa Stockdale, Zita-Rose Manjaly-Thomas, Samantha Vermaak, Iman Satti, Paul Moss, Helen McShane

Abstract

Background: There is an urgent need for an improved tuberculosis 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. Optimization of this model is required.

Methods: Healthy BCG-naive 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, skin biopsy of 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 with standard-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 tuberculosis vaccine effectiveness with this optimized model could contribute to vaccine selection for efficacy trials.

Clinical trials registration: NCT02088892.

Keywords: BCG; anti-mycobacterial immunity; human mycobacterial challenge model; tuberculosis; vaccine effectiveness.

© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Study profile. CONSORT (Consolidated Standard of Reporting Trials) flow diagram, showing volunteer recruitment and follow up. Volunteers were allocated to groups A and B in parallel. Once enrollment was completed for both groups, subjects were enrolled in groups C and D. aA replacement volunteer was required in group B because it was unclear whether bacille Calmette-Guérin (BCG) had been administered intradermally or subcutaneously in a volunteer who had no signs of local inflammatory response to the BCG challenge, resulting in 11 volunteers who received the group B intervention; bThe group B volunteer who lacked a local response to BCG was excluded from analysis, resulting in 10 volunteers for analysis in group B. This volunteer was followed up for 28 days after challenge, and there were no safety concerns.
Figure 2.
Figure 2.
Local reactogenicity. Maximum diameters of redness (A) and swelling (B) at the challenge site, with mean values and 95% confidence intervals. Mean values were compared with 1-way analysis of variance, with the Tukey test for multiple comparisons. The difference in mean diameter was not statistically significant between groups (P > .05). Dots represent values for individual volunteers.
Figure 3.
Figure 3.
Recovery of bacille Calmette-Guérin (BCG) by culture on solid agar (A), and BCG quantitation by quantitative polymerase chain reaction (B) in skin biopsy specimens obtained from 40 healthy volunteers challenged with standard-dose BCG SSI (group A) or BCG TICE (group B) or high-dose BCG SSI (group C) or BCG TICE (group D). Dots represent individual volunteers, and black lines show median values. **P < .01 and ***P < .00, by the Mann–Whitney U test. Abbreviation: CFU, colony-forming units.
Figure 4.
Figure 4.
Ex vivo interferon γ enzyme-linked immunospot responses to stimulation with purified protein derivative (PPD; A) and relationship of day 14 PPD responses to the number of bacille Calmette-Guérin (BCG) detected in skin biopsy specimens by quantitative polymerase chain reaction from volunteers given a standard-dose challenge (B) and those given a high-dose challenge (C). Dots represent individual volunteers, and black lines show median values. *P < .05 and **P < .01, by the Mann–Whitney U test. Abbreviations: PBMC, peripheral blood mononuclear cell; SFC, spot-forming cell.

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Source: PubMed

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