Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis

Abstract

Background: A vaccine to interrupt the transmission of tuberculosis is needed.

Methods: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01_E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01_E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01_E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both.

Results: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01_E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01_E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01_E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.

Conclusions: M72/AS01_E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).

Figure 1. Study flow

ATP = according to protocol, N = number of participants, TB = tuberculosis *Participants eliminated from the ATP efficacy cohort: administration of vaccine forbidden in the protocol (19), randomization error (2), randomization code broken at the investigator site (1), study vaccine not administered according to protocol (3), did not receive two vaccine doses (236), did not enter the efficacy evaluation period one month post-dose 2 (11), active tuberculosis (any case definition) diagnosed up to one month post-dose 2 (1), administration of medication forbidden by the protocol (2), non-compliance with vaccination schedule (3), did not meet inclusion/exclusion criteria (7). **Participants eliminated from the ATP immunogenicity cohort: administration of vaccine forbidden in the protocol (4), sputum Mtb positive at baseline (1), did not meet inclusion/exclusion criteria (1), concomitant infection (active TB) related to the vaccine which may influence immune response (1), concomitant infection (became HIV -infected) not related to the vaccine which may influence immune response (7), non- compliance with the vaccination schedule (3), non-compliance with the blood sampling schedule (9), essential serological data missing (all post-vaccination time points month 2 and month 12 missing) (15), did not receive two vaccine doses (15).

Figure 2. Kaplan- Meier estimate of definite pulmonary tuberculosis disease not associated with HIV -infection (first case definit ion) (According to protocol efficacy cohort)

The decreased number at risk after 24 months reflects the participants for whom follow-up after this time point had not occurred at the data lock point. HR = hazard ratio CI = confidence interval TB = tuberculosis