Phase 2b placebo-controlled trial of M72/AS01(E) candidate vaccine to prevent active tuberculosis in adults

BACKGROUND: A tuberculosis vaccine to interrupt transmission is urgently needed. We assessed the safety and efficacy of the candidate tuberculosis vaccine, M72/AS01(E), 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/AS01(E) 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/AS01(E) 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/AS01(E) was associated with a clinically acceptable safety profile and provided 54.0% protection for Mtb-infected adults against active pulmonary tuberculosis disease.