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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.

Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

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