Understanding BCG is the key to improving it.

The need for improved tuberculosis control remains a global health priority. The most cost-effective long-term solution for any infectious disease epidemic is effective vaccination. The only licensed vaccine against tuberculosis, BCG, when administered at birth, is highly effective at preventing disseminated disease in childhood. However, the protection conferred against pulmonary disease is highly variable, and a more effective and consistent vaccination regimen is urgently needed [1]. Leading approaches to developing a better tuberculosis vaccine include boosting BCG with a subunit vaccine incorporating one or several antigens from Mycobacterium tuberculosis in a potent antigen delivery system, and developing a recombinant strain of BCG (or another whole mycobacterial vaccine) to replace BCG with a safer and more effective vaccine [2]. The recent failure of the MVA85A trial to enhance efficacy in BCG-vaccinated South African infants suggests that improving on BCG-induced protection, at least in infants, may not be easy [3]. One of the challenges is the underlying variability in BCG efficacy against pulmonary disease, across different geographical areas and different age groups. Understanding the underlying mechanisms for this variability is important, both to optimize the delivery of BCG (or newer BCG replacement vaccines) and to facilitate the development of booster vaccines that overcome this variability. Over the last decade or so, many different hypotheses have been proposed to explain the variability in efficacy observed in different clinical trials. These include differences in BCG andM. tuberculosis strains, host genetics, nutrition, coinfection with helminths, and exposure to nontuberculous mycobacteria (NTM). Whereas the relative importance of these different mechanisms may differ by geographical area, and more than one explanation may be involved, there is increasing evidence for a role of exposure to nontuberculous mycobacteria in explaining at least some of the variability. Two potentially complementary mechanisms have been proposed to explain how exposure to NTM might interfere with BCG efficacy: masking and blocking. The masking hypothesis is best illustrated by elegant work by Black and colleagues, where anti-mycobacterial immunity in BCG-naiveadolescentsintheUnitedKingdom and Malawi was evaluated, prior to and after BCG vaccination [4]. In the United Kingdom, baseline immunity was very low and there was a significant rise in antimycobacterial immunity after BCG vaccination. In contrast, in Malawi, baseline, prevaccination immunity was high. This was thought to be induced by NTM exposure as subjects with M. tuberculosis exposure had been excluded. Incremental rise in antimycobacterial immunity after BCG vaccination was much lower in these African adolescents, suggesting that the NTM induced immunity “masks” the effect of BCG vaccination, and that this preexisting immunity cannot be boosted with BCG. The “blocking” hypothesis suggests a more active immunological mechanism whereby the preexisting antimycobacterial immunity induced by NTM “blocks” the replication of BCG and therefore inhibits any protective effect. BCG is a live attenuated vaccine and efficacy is dependent on replication. In mice, preexposure to NTM can inhibit the protective effect of BCG, but interestingly, preexposure to NTM did not affect the efficacy of a (nonreplicating) subunit vaccine, a finding that is encouraging for the development of subunit booster vaccines [5]. In this issue of Clinical Infectious Diseases, Mangtani and colleagues provide further corroborating evidence for a role for NTM exposure in explaining the variability in BCG efficacy. They conducted a systematic review of all reported BCG efficacy trials, and examined associations Received 18 November 2013; accepted 24 November 2013; electronically published 13 December 2013. Correspondence: Helen McShane, PhD, FRCP, The Jenner Institute, University of Oxford, Old Road Campus Research Bldg, Roosevelt Drive, Oxford OX3 7DQ, UK (helen.mcshane@ ndm.ox.ac.uk). Clinical Infectious Diseases 2014;58(4):481–2 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/cid/cit793