Showing papers by "Angela M. Minassian published in 2012"

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

Abstract: The tuberculosis vaccine field has had to rely on preclinical animal challenge models of Mycobacterium tuberculosis infection or on the development of in vitro models of M. tuberculosis killing as surrogate measures of vaccine efficacy [1]. However, it remains unknown how predictive these are of human in vivo protection, and the development of a relevant in vivo human challenge model would be a significant advancement for the field. The existence of human challenge models for pathogens, such as malaria, influenza, dengue, and typhoid, has greatly facilitated vaccine development [2–5]. However, the ethical barriers to challenging humans with virulent replicating mycobacteria have thus far limited the development of a human M. tuberculosis challenge model. Here, we introduce a novel in vivo bacille Calmette-Guerin (BCG) challenge model using Mycobacterium bovis BCG vaccination as a surrogate for M. tuberculosis infection, based on the hypothesis that an effective vaccine against M. tuberculosis should also reduce the replication of BCG. Published preclinical studies support the hypothesis that vaccine-induced suppression of a BCG challenge in small animals is comparable to that of an M. tuberculosis challenge, and the vaccine most commonly assessed in such challenge studies is BCG [6–8]. BCG is a feasible challenge agent for human use: it is a safe replicating mycobacterium (with 99.95% sequence homology relative to live M. bovis) [9], it causes a self-contained limited infection in immunocompetent animals and humans, and it is licensed for human use. We have recently demonstrated that live BCG persists in murine skin for ≥4 weeks and that intradermal BCG vaccination consistently protects against an intradermal BCG challenge—an effect that is independent of vaccination dose, route, or vaccination-challenge interval. We have also shown in the mouse model that efficacy of BCG vaccination against subsequent intradermal BCG challenge is comparable to known vaccine efficacy against aerosol M. tuberculosis challenge, supporting the relevance of a mycobacterial skin challenge to an aerosol M. tuberculosis challenge [10]. We now describe the application of these preclinical findings to a human BCG challenge model, in which the kinetics of BCG were assessed in the skin of healthy BCG-naive volunteers. Few studies have attempted to detect BCG at the vaccination site, other than in the context of a suppurative lesion complicating vaccination, and none have actually quantified the level of live BCG at these sites [11]. Here, we show that live BCG persists in human skin for up to 1 month and that there is a spectrum of mycobacterial growth or protection within a group with prior BCG vaccination, which may reflect the spectrum of protection conferred by BCG against tuberculosis in humans [12]. This BCG challenge model has the potential to enable proof-of-concept vaccine efficacy screening for the first time in humans and to allow the identification of an immunological profile associated with reduced bacterial load in the skin.