BackgroundRecent Mycobacterium tuberculosis (M.tb) infection predisposes to tuberculosis disease, the leading global infectious disease killer. We tested safety andefficacy of H4:IC31® vaccination or Bacille Calmette-Guerin (BCG) revaccination for prevention of M.tb infection. MethodsQuantiFERON-TB Gold In-tube (QFT) negative, HIV-uninfected, remotely BCG-vaccinated adolescents were randomized 1:1:1 to placebo, H4:IC31® or BCG revaccination (NCT02075203). Primary outcomes were safety and acquisition of M.tb infection, defined by initial QFT conversion tested 6-monthly over two years. Secondary outcomes were immunogenicity and sustained M.tb infection, defined by sustained QFT conversion without reversion three and six months post-conversion. Statistical significance for efficacy proof-of-concept was set at 1-sided p<0.10.Results990 participants were enrolled. Both vaccines had acceptable safety profiles and were immunogenic. QFT conversion occurred in 134 and sustained conversion in 82 participants. Neither H4:IC31® nor BCG prevented initial QFT conversion, with efficacy point estimates of 9.4% (95% confidence interval: -36.2, 39.7; one-sided p=0.32) and 20.1% (-21.0, 47.2; one-sided p=0.14), respectively. However, BCG did prevent sustained QFT conversion with an efficacy of 45.4% (6.4, 68.1; one-sided p=0.013); H4:IC31® efficacy was 30.5% (-15.8, 58.3; one-sided p=0.08). QFT reversion rate from positive to negative was 46% in BCG, 40% in H4:IC31 and 25% in placebo recipients. ConclusionsThis first proof-of-concept, prevention of M.tb infection trial showed that sustained infection can be prevented by vaccination in a high-transmission setting and confirmed feasibility of this strategy to inform clinical development of new vaccine candidates. Evaluation of BCG revaccination to prevent tuberculosis disease in M.tb- uninfected populations is warranted.

A long-term goal is to characterize the full range of genetic diversity within Streptococcus pyogenes as it exists in the world today. Since the emm locus is subject to strong diversifying selection, emm type was used as a guide for identifying a genetically diverse set of strains. This report contains a description of multilocus sequence typing based on seven housekeeping loci for 495 isolates representing 158 emm types, yielding 238 unique combinations of sequence type and emm type. A genotypic marker for tissue site preference (emm pattern) revealed that only 17% of the emm types displayed the marker representing strong preference for infection at the throat and that 39% of emm types had the marker for skin tropism, whereas 41% of emm types harbored the marker for no obvious tissue site preference. As a group, the emm types bearing the emm pattern marker indicative of no obvious tissue site preference were far less likely to have two distinct emm types associated with the same sequence type than either of the two subpopulations having markers for strong tissue tropisms (P < 0.002). In addition, all genetic diversification events clearly ascribed to a recombinational mechanism involved strains of only two of the emm pattern-defined subpopulations, those representing skin specialists and generalists. The findings suggest that the population genetic structure differs for the tissue-defined subpopulations of S. pyogenes. The observed differences may partly reflect differential host immune selection pressures.

Implementation of optimized procedures and a more rigorous QuantiFERON-TB conversion definition (an increase from IFN-γ <0.2 to >0.7 IU/ml) would allow more definitive detection of recent Mtb infection and potentially improve identification of those more likely to develop disease.

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.

Summary Background Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design. Methods Adult volunteers aged 18–59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov , NCT02735590 . Findings 20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25–6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3H...

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Background Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high. Methods We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18-50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-γ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 10⁵ colony forming units [CFU] of Danish strain 1331 in 0•1 mL diluent) or MTBVAC (5 × 10⁵ CFU in 0•1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2•5 × 10⁵ CFU in 0•05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2•5 × 10³ CFU, 2•5 × 10⁴ CFU, and 2•5 × 10⁵ CFU in 0•05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with ClinicalTrials.gov, number NCT02729571.

Gonorrhea is a sexually transmitted disease causing growing concern, with a substantial increase in reported incidence over the past few years in the United Kingdom and rising levels of resistance to a wide range of antibiotics. Understanding its epidemiology is therefore of major biomedical importance, not only on a population scale but also at the level of direct transmission. However, the molecular typing techniques traditionally used for gonorrhea infections do not provide sufficient resolution to investigate such fine-scale patterns. Here we sequenced the genomes of 237 isolates from two local collections of isolates from Sheffield and London, each of which was resolved into a single type using traditional methods. The two data sets were selected to have different epidemiological properties: the Sheffield data were collected over 6 years from a predominantly heterosexual population, whereas the London data were gathered within half a year and strongly associated with men who have sex with men. Based on contact tracing information between individuals in Sheffield, we found that transmission is associated with a median time to most recent common ancestor of 3.4 months, with an upper bound of 8 months, which we used as a criterion to identify likely transmission links in both data sets. In London, we found that transmission happened predominantly between individuals of similar age, sexual orientation, and location and also with the same HIV serostatus, which may reflect serosorting and associated risk behaviors. Comparison of the two data sets suggests that the London epidemic involved about ten times more cases than the Sheffield outbreak.