Journal of Infectious Diseases
Volume 205 Issue 7 April 1, 2012
http://www.journals.uchicago.edu/toc/jid/current

EDITORIAL COMMENTARIES
Hazel M. Dockrell
Editor’s Choice: A New Challenge for the Tuberculosis Vaccine Community?
J Infect Dis. (2012) 205(7): 1029-1031 doi:10.1093/infdis/jis016

Extract
The tuberculosis vaccine community has much to occupy it at this time. Two recombinant BCG vaccines currently in clinical trials are designed to improve the protection given by Mycobacterium bovis bacille Calmette-Guérin (BCG) and hoped to be safer in human immunodeficiency virus (HIV)–infected infants as are a number of novel vaccines designed to boost the immunity given by BCG (or an improved priming vaccine), including viral vectors expressing key antigens of M. tuberculosis and fusion proteins in adjuvant [1]. The pipeline of vaccines in phase I and phase II trials is supported by a number of promising vaccines in early-stage development. However, even in settings with the highest incidence of tuberculosis, large-scale and very costly trials will be needed to determine the efficacy of a new tuberculosis vaccine. The development of these vaccines is hampered by our current inability to identify biosignatures or correlates of protection that would be induced by a protective tuberculosis vaccine. This limitation has been identified as a roadblock by many in the field, including in the new Integrated Roadmap for Tuberculosis Research published by the Stop TB Partnership and the World Health Organization in November 2011 [2]. Minassian et al [3], in this issue of the Journal, reports a new approach that could lead to new insights, in which BCG vaccination has been used as a challenge.

In other fields, an infectious challenge has been used to test new vaccines, bypassing the need for correlates of protection (eg, for malaria using bites from infected mosquitoes [4], influenza [attempted as far back as 1918 and successful in 1936] [5], diarrhea-inducing enterotoxigenic Escherichia coli [6], dengue [7], Campylobacter jejuni [8 …

MAJOR ARTICLES AND BRIEF REPORTS
BACTERIA
Angela M. Minassian, Iman Satti, Ian D. Poulton, Joel Meyer, Adrian V. S. Hill, and Helen McShane
Editor’s Choice: A Human Challenge Model for Mycobacterium tuberculosis Using Mycobacterium bovis Bacille Calmette-Guérin
J Infect Dis. (2012) 205(7): 1035-1042 doi:10.1093/infdis/jis012

Abstract
(See the editorial commentary by Dockrell)

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.