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SummaryWe report a large study of the effect of BCG vaccination on the in vitro 6-day whole blood interferon-gamma (IFN-g) response to antigens from eight species of mycobacteria among schoolchildren in south-eastern England, where bacille Calmette-Guérin (BCG) vaccination is highly protective against pulmonary tuberculosis, and among young adults in northern Malawi, where BCG vaccination is not protective. In the UK children, BCG induced an appreciable increase in IFN-g response to antigens from most species of mycobacteria. The degree of change was linked to the relatedness of the species to Mycobacterium bovis BCG, and provides further evidence of the cross-reactivity of mycobacterial species in priming of the immune system. IFN-g responses to purified protein derivatives (PPDs) from M. tuberculosis and environmental mycobacteria were more prevalent in the Malawian than the UK group prior to vaccination; BCG vaccination increased the prevalence of responses to these PPDs in the UK group to a level similar to that in Malawi. There was no evidence that the vaccine-induced change in IFN-g response was dependent upon the magnitude of the initial response of the individual to environmental mycobacteria in the United Kingdom or in Malawi. These observations should assist the development and interpretation of human clinical trials of new vaccines against M. tuberculosis in areas of both low and high exposure to environmental mycobacteria.

SUMMARYThe immune responses of schoolchildren in southeast England to Mycobacterium tuberculosis and other species of mycobacteria were studied prior to vaccination with bacille Calmette-Guérin (BCG). Data are presented for tuberculin (Heaf) skin test and interferon-g (IFN-g ) responses to M. tuberculosis purified protein derivative (PPD), and IFN-g responses to PPDs from eight other environmental mycobacteria, measured in 424 schoolchildren (13-15 years of age). Responses to M. tuberculosis PPD were detected in 27% of schoolchildren by in vitro IFN-g response and in 20% by the Heaf test. IFN-g responses were more prevalent to PPDs from species of mycobacteria other than M. tuberculosis , predominantly those of the MAIS complex and M. marinum (45-60% responders). Heaf test and IFN-g responses were associated ( P < 0·001) for M. tuberculosis , MAIS and M. marinum . These findings have implications for appropriate implementation of vaccination against tuberculosis.

Cutaneous diphtheria is endemic in tropical countries but unusual in the United Kingdom. Four cases occurred in the United Kingdom within 2 months in 2002. Because cutaneous diphtheria causes outbreaks of both cutaneous and pharyngeal forms, early diagnosis is essential for implementing control measures; high diphtheria vaccination coverage must also be maintained.

f Two Southeast Asian students attending the same school in the United Kingdom presented with pulmonary tuberculosis. An epidemiological investigation failed to link the two cases, and drug resistance profiles of the Mycobacterium tuberculosis isolates were discrepant. Whole-genome sequencing of the isolates found them to be genetically identical, suggesting a missed transmission event.T uberculosis is a major global public health challenge, with an incidence of 8.8 million new cases and 1.4 million deaths in 2010 (1). The United Kingdom is a low-prevalence country, with 8,963 new cases reported in 2011, giving an overall incidence of 14.4 cases per 100,000 population per year (2). The majority of cases (74%) occur in persons born outside the United Kingdom, and the rate of tuberculosis is almost 21 times higher in nonUnited Kingdom-born than United Kingdom-born individuals. The United Kingdom Health Protection Agency collects clinical and epidemiological information about all tuberculosis cases through the National Enhanced Tuberculosis Surveillance system. In 2010, a national strain typing service was introduced in order to aid in the investigation of outbreaks. This uses the 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeats (MIRU-VNTRs) to type all Mycobacterium tuberculosis isolates that are submitted to the reference laboratory (2). M. tuberculosis is a clonal organism, and accumulating evidence suggests that conventional typing may be insufficient to discriminate between closely related strains within a given lineage. Whole-genome sequencing provides the ultimate resolution of genomic data and has been shown to be superior to MIRU-VNTR typing in the investigation of a large outbreak in Canada (3). Here, we describe the use of whole-genome sequencing to investigate a suspected tuberculosis outbreak in a language school in Cambridge, United Kingdom.Case histories. On 5 November 2010, a 22-year-old South Korean man presented to our hospital with smear-positive pulmonary tuberculosis. He had no medical history and no known contact with tuberculosis and was studying at a local English language school. Treatment was commenced with standard antituberculosis therapy (rifampin, isoniazid, pyrazinamide, and ethambutol), and he was discharged from the hospital on 17 November 2010. Antibiotic susceptibility results subsequently revealed resistance to isoniazid, prothionamide, and streptomycin, and moxifloxacin was substituted for isoniazid.On 22 November 2010, a 24-year-old Japanese man presented to our hospital with smear-positive pulmonary tuberculosis. He had no medical history and no known contact with tuberculosis and was also studying at the same language school. Treatment was commenced with standard antituberculosis therapy. Progress was complicated by hepatitis (which necessitated temporary interruption of rifampin, isoniazid, and pyrazinamide and the addition of streptomycin to ethambutol), a spontaneous pneumothorax (which resolved), and prolonged fever. Antimicrobial suscept...