BACKGROUNDResults of an earlier analysis of a trial of the M72/AS01 E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. METHODSFrom August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01 E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01 E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01 E or placebo. RESULTSA total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01 E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01 E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01 E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONSAmong adults infected with M. tuberculosis, vaccination with M72/AS01 E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; Clini-calTrials.gov number, NCT01755598.

Background:A tuberculosis vaccine to interrupt transmission is urgently needed. We assessed the safety and efficacy of the candidate tuberculosis vaccine, M72/AS01E, against progression to bacteriologically-confirmed active pulmonary tuberculosis disease in adults with latent Mycobacterium tuberculosis (Mtb) infection. Methods:In a randomized, double-blind, placebo-controlled, phase 2b trial conducted in Kenya, South Africa and Zambia, human immunodeficiency virus (HIV)-negative adults aged 18-50 years with latent Mtb infection (positive by interferon-gamma release assay) were randomized (1:1) to receive two doses of either M72/AS01E or placebo intramuscularly on days 0 and 30. Clinical suspicion of tuberculosis was confirmed from sputum using a polymerase chain reaction test and/or mycobacterial culture. Results:This paper reports the primary analysis, conducted after a mean follow-up of 2.3 years. 1786 participants received M72/AS01E and 1787 received placebo. In the vaccine group, 10 cases met the primary case definition (bacteriologically-confirmed active pulmonary tuberculosis confirmed prior to treatment, not associated with HIV infection) versus 22 cases in the placebo group (0.3 vs. 0.6 cases per 100 person-years, respectively): vaccine efficacy 54.0% (90% confidence interval 13.9-75.4; 95%CI 2.9-78.2; p=0.04). Solicited and unsolicited adverse events within 7 days post-injection were more frequent among M72/AS01E recipients (91.2%) than placebo recipients (68.9%), the difference attributed mainly to injection site reactions and flu-like symptoms. Serious adverse events, potential immune-mediated diseases and deaths occurred with similar low frequencies between groups. Conclusions:M72/AS01E was associated with a clinically acceptable safety profile and provided 54.0% protection for Mtb-infected adults against active pulmonary tuberculosis disease.

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We aimed to model the incidence of infection with Mycobacterium tuberculosis among adults using data on infection incidence in children, disease prevalence in adults, and social contact patterns. We conducted a cross-sectional face-to-face survey of adults in 2011, enumerating “close” (shared conversation) and “casual” (shared indoor space) social contacts in 16 Zambian communities and 8 South African communities. We modeled the incidence of M. tuberculosis infection in all age groups using these contact patterns, as well as the observed incidence of M. tuberculosis infection in children and the prevalence of tuberculosis disease in adults. A total of 3,528 adults participated in the study. The reported rates of close and casual contact were 4.9 per adult per day (95% confidence interval: 4.6, 5.2) and 10.4 per adult per day (95% confidence interval: 9.3, 11.6), respectively. Rates of close contact were higher for adults in larger households and rural areas. There was preferential mixing of close contacts within age groups and within sexes. The estimated incidence of M. tuberculosis infection in adults was 1.5–6 times higher (2.5%–10% per year) than that in children. More than 50% of infections in men, women, and children were estimated to be due to contact with adult men. We conclude that estimates of infection incidence based on surveys in children might underestimate incidence in adults. Most infections may be due to contact with adult men. Treatment and control of tuberculosis in men is critical to protecting men, women, and children from tuberculosis.

BackgroundThe Stop TB Partnership target for tuberculosis is to have reduced the prevalence of tuberculosis by 50% comparing 2015 to 1990. This target is challenging as few prevalence surveys have been conducted, especially in high burden tuberculosis and HIV countries. Current tuberculosis control strategies in high HIV prevalent settings are therefore based on limited epidemiological evidence and more evidence is needed from community-based surveys to inform improved policy formulation.Methods and Findings8044 adults were sampled from 2 sub-districts (wards) in Lusaka province, Zambia. Questionnaires were used to screen for symptoms, respiratory samples were obtained for culture and oral secretions collected for HIV testing. 79 individuals were found to have Mycobacterium tuberculosis in their sputum, giving an adjusted overall prevalence of tuberculosis of 870/100,000 (95% CI 570–1160/100,000). The adjusted overall prevalence of HIV was 28.61% (95% CI 26.04–31.19). HIV- infection was significantly associated with prevalent tuberculosis (Adj OR 2.3, 95% CI 1.42–3.74) and the population attributable fraction of HIV for prevalent tuberculosis was 36%. Symptoms such as prolonged cough (adj OR 12.72, 95% CI 7.05–22.94) and fever (Adj OR 2.04, 95%CI 1.23–3.39), were associated with prevalent tuberculosis, but 8 (10%) individuals with prevalent tuberculosis denied having any symptoms at all and only 34 (43%) would have been classified as a TB suspect by current guidelines.ConclusionsUndiagnosed tuberculosis is a challenge for tuberculosis control and new approaches are needed if we are to reach international targets. Epidemiological studies can inform screening algorithms for both detection and prevention of active tuberculosis.