A Human Challenge Model for Mycobacterium tuberculosis Using Mycobacterium bovis Bacille Calmette-Guérin

Abstract

(See the editorial commentary by Dockrell, on pages .)Background. There is currently no safe human challenge model of Mycobacterium tuberculosis infection to enable proof-of-concept efficacy evaluation of candidate vaccines against tuberculosis. In vivo antimycobacterial immunity could be assessed using intradermal Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination as a surrogate for M. tuberculosis infection.Methods. Healthy BCG-naive and BCG-vaccinated volunteers were challenged with intradermal BCG. BCG load was quantified from skin biopsy specimens by polymerase chain reaction (PCR) and culture colony-forming units. Cellular infiltrate was isolated by suction blisters and examined by flow cytometry. Prechallenge immune readouts were correlated with BCG load after challenge.Results. In BCG-naive volunteers, live BCG was detected at the challenge site for up to 4 weeks and peaked at 2 weeks. Infiltration of mainly CD15+ neutrophils was observed in blister fluid. In previously BCG-vaccinated individuals, PCR analysis of skin biopsy specimens reflected a degree of mycobacterial immunity. There was no significant correlation between BCG load after challenge and mycobacterial-specific memory T cells measured before challenge by cultured enzyme-linked immunospot assay.Conclusions. This novel experimental human challenge model provides a platform for the identification of correlates of antimycobacterial immunity and will greatly facilitate the rational down-selection of candidate tuberculosis vaccines. Further evaluation of this model with BCG and new vaccine candidates is warranted.

Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes

“…Little is known about how long BCG stays viable in the human body. Fortunately, however, a very recent study by Minassian et al (31) reports that 4 wk after vaccination, only 50% of individuals still displayed viable BCG at the vaccination site. Although we cannot fully exclude a low BCG persistence in a minority of the volunteers, it is to be expected that in most of them, all the microorganisms were cleared after 3 mo.…”

TB or Not TB: That Is No Longer the Question

“…This has been a very important tool in studying protection in other infectious diseases, such as malaria and cholera. There have been preliminary studies using intradermal BCG as a live challenge and measuring bacterial survival after excision (187). With a genetically attenuated Mtb strain, such as an auxotroph unable to grow without essential nutrients, and with a conditional promoter, such as tet-on, allowing growth only in the presence of doxycycline, assuring that the challenge would die when the drug is removed, one could potentially create a very safe challenge strain.…”

Design of tuberculosis vaccine trials under financial constraints

“…A human challenge model is being used widely in malaria vaccine research where a 3-day course of antimalarials is curative, but for TB there are serious safety concerns that prohibit human challenge. Only one challenge model has been tested -using BCG intradermally as the challenge strain [18]. Further challenge studies with attenuated M. tuberculosis strains at lung level could be very informative for vaccine research, increasing its efficiency especially for testing POI candidates, but safety of the model would have to be assured first.…”