Final Analysis of a Trial of M72/AS01_E Vaccine to Prevent Tuberculosis

Abstract

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.

Cell-Mediated Immune Responses to in vivo-Expressed and Stage-Specific Mycobacterium tuberculosis Antigens in Latent and Active Tuberculosis Across Different Age Groups

“…To boost or replace BCG, multiple TB vaccine candidates have been proposed and are being evaluated in different higher end preclinical or clinical phase 1 and phase 2 studies (7). Recently one subunit vaccine candidate, M72/AS01E, induced significant protection from developing TB in a LTBI population (8,9). Although the numbers of prevented cases were relatively low as yet (10 TB cases in the M72/AS01E group vs. 22 TB cases in the placebo group, a vaccine efficacy of 54%), the outcome of this phase IIb trial supports the power of rational Mtb antigen-based subunit TB vaccine development.…”

“…However, the immune response of adolescents is not often analyzed as a separate entity but merged with that found in either children (48,64) or adults (37). The need for carefully considering different age groups is supported by the M72/AS01E efficacy trial results, which showed that the highest vaccine efficacy in preventing active TB among LTBI was in individuals of 25 years of age or younger, after 2.5 years of follow up (8,9). This observed age-effect has been explained by possibly different timing of primary Mtb infection occurrence.…”

“…This observed age-effect has been explained by possibly different timing of primary Mtb infection occurrence. Based on this reasoning, younger LTBI due to a more-recent primary Mtb infection would be less likely to have the infection under immune control, and therefore could benefit more from boosting immune responses by the administration of M72/AS01E (8,9). In our cohort, IFN-γ producing cells were not compromised by active TB disease or age (or time of Mtb exposure), since blood cells of all groups were similarly effective in secreting IFN-γ in response to antigens present in the QuantiFERON-TB Gold test [ESAT-6/CFP-10/TB-7.7(p4)] ( Table 1) and to other specific Mtb antigens (Figure 1).…”

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

“…The majority of individuals successfully control Mycobacterium tuberculosis (Mtb) infection in a clinically asymptomatic state termed latent TB infection (LTBI)(1). Individuals with LTBI are defined as having a positive tuberculin skin test (TST) and/or Interferon-gamma Release Assay (IGRA), a normal chest radiograph and the absence of clinical signs and symptoms of disease(2). Latently-infected individuals are generally thought to contain Mtb within granulomatous lesions in the lung without completely eradicating bacteria, although direct evidence for the persistence of Mtb in human LTBI is lacking.…”

Twenty‐five years of Respirology: Advances in respiratory infections and tuberculosis

“…Recently, a phase 2b trial of the M72/AS01 E vaccine in Africa showed vaccine efficacy of 50% at 3 years for MTB-infected, HIV-negative adults against active pulmonary TB, representing a major breakthrough. 19 TB control programmes and health services need to be strengthened to realize the potential of these recent scientific advances. Political leadership and accountability, sustainable funding and investment in research and development, and, not least, addressing the societal and poverty-related drivers of the TB epidemic will be vital in order to achieve WHO's ambitious goal to 'End TB by 2030'.…”