EDITORIAL COMMENTARY

Understanding BCG Is the Key to Improving It

Helen McShane The , , (See the Major Article by Mangtani et al on pages 470–80.)

Keywords. BCG; ; efficacy.

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

EDITORIAL COMMENTARY • CID 2014:58 (15 February) • 481 with efficacy including immunological that exposure to NTM can some settings and not others allows us evidence of mycobacterial exposure prior happen very early in life and that with- to optimize BCG administration. The de- to vaccination and BCG strain. holding BCG until 4 months of age velopment of appropriate immunological This analysis was restricted to the most results in measurable antimycobacterial tools with which to quantify NTM expo- methodologically rigorous trials, with the immunity, presumably induced by NTM sure would allow us confirm or refute the caveat that many of these trials were con- [7]. Although at 9 months, antimycobac- role of NTM in explaining the variability ducted many decades ago (and most terial immunity was comparable between in efficacy of BCG, and furthermore to papers were published before 1973), in infants vaccinated either at birth or at 4 use such tools to optimize the develop- an era with different standards for statis- months in this Gambian study, we do ment of more effective and more consis- tical and methodological rigor. The not know which aspects of immunity tent vaccination regimes. authors find that the greatest average effi- correlate with protection, and it would be cacy of BCG was when BCG was admin- prudent to recommend BCG vaccination Note istered to neonates (rate ratio [RR], 0.41; as soon as possible after birth. However, fi – Potential conflicts of interest. Author certifies 95% con dence interval [CI], .29 .58]) this recommendation cannot be applied fl fi no potential con icts of interest. or when BCG was administered to school- in areas with high human immunode - The author has submitted the ICMJE Form for age children with stringent tuberculin ciency virus (HIV) prevalence, as exclud- Disclosure of Potential Conflicts of Interest. Con- fl testing (as in the British Medical Re- ing HIV prior to BCG is icts that the editors consider relevant to the content of the manuscript have been disclosed. search Council study in the 1950s [6]) recommended in those regions. Just as (random-effects RR, 0.26; 95% CI, important, this theory suggests that the References 0.18–.37). They confirm previous find- effects of prior NTM exposure on candi- ings that efficacy correlates with latitude date tuberculosis vaccines in develop- 1. Colditz GA, Brewer TF, Berkey CS, et al. Effi- and increases with increasing trial site ment should also be evaluated. The cacy of BCG vaccine in the prevention of tu- fi berculosis. Meta-analysis of the published distance from the equator. In a univariate ef cacy of the live BCG replacement vac- literature. JAMA 1994; 271:698–702. analysis, these 2 factors (distance from cines may also be affected by prior expo- 2. Brennan MJ, Thole J. Tuberculosis vaccines: a the equator and age at vaccination/tuber- sure to NTM, in the same way as BCG. strategic blueprint for the next decade. Tuber- 2012 – culin testing stringency) explained most The efficacy of subunit, nonreplicating, culosis (Edinb) ; 92(suppl 1):S6 13. 3. Tameris MD, Hatherill M, Landry BS, et al. fi of the between-trial variability in ef - booster vaccines may not be inhibited by Safety and efficacy of MVA85A, a new tuber- cacy; using a 2-variable meta-regression such exposure, but will have to improve culosis vaccine, in infants previously vaccinated model, these 2 factors explained all of the upon protection induced by BCG and with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013; 381:1021–8. between-trial variability. Importantly, the NTM. Modeling NTM exposure in pre- 4. Black GF, Weir RE, Floyd S, et al. BCG- authors also find that BCG strain does clinical animal models is extremely diffi- induced increase in interferon-gamma re- not explain the variability in BCG effica- cult, as it is likely that route, dose, NTM sponse to mycobacterial antigens and efficacy fi of BCG vaccination in Malawi and the UK: cy. This analysis also con rmed previous strain, and NTM virulence varies by age two randomised controlled studies. Lancet findings of a strong protective effect of and geographical location. We need to 2002; 359:1393–401. BCG against meningeal or miliary dis- measure NTM-induced immunity in the 5. Brandt L, Feino Cunha J, Weinreich Olsen A, ease. Although the authors are rightly ongoing clinical vaccine trials, but such et al. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental my- cautious with their interpretation of studies are limited by the lack of immu- cobacteria block multiplication of BCG and these findings, given the large number of nological tools with which to measure induction of protective immunity to tubercu- 2002 – variables used in the multivariable analy- specific NTM-induced immunity. At- losis. Infect Immun ; 70:672 8. fi 6. Hart PD, Sutherland I. BCG and vole bacillus ses (7) compared with the number of tempts to identify NTM-speci c antigens vaccines in the prevention of tuberculosis in studies (18), these findings add further and NTM-specific epitopes within the adolescence and early adult life. Br Med J support to existing evidence from human immunodominant antigens currently in- 1977; 2:293–5. 7. Burl S, Adetifa UJ, Cox M, et al. Delaying and animal studies that prior NTM expo- cluded in subunit booster vaccines have bacillus Calmette-Guerin vaccination from sure interferes with the efficacy of BCG, been made, but are not easy due to very birth to 4 1/2 months of age reduces post- and that BCG is most effective in myco- significant genetic sequence overlap be- vaccination Th1 and IL-17 responses but bacterially naive hosts. tween NTM and M. tuberculosis complex leads to comparable mycobacterial responses at 9 months of age. J Immunol 2010; 185: If this theory is correct, there are some organisms [8]. 2620–8. important practical implications. We This work takes us one step forward 8. Checkley AM, Wyllie DH, Scriba TJ, et al. fi fi should optimize deployment of BCG to in the aim of developing an effective tu- Identi cation of antigens speci c to non- tuberculous mycobacteria: the Mce family of administration as close to birth as possi- berculosis vaccine regimen for global proteins as a target of T cell immune respons- ble. We know from studies conducted in use. Understanding why BCG works in es. PLoS One 2011; 6:e26434.

482 • CID 2014:58 (15 February) • EDITORIAL COMMENTARY