Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis

Original: N Engl J Med 2019; 381: 2429-2439

Author(s): Dereck R. Tait, Mark Hatherill, Olivier Van Der Meeren et al

Reviewer: Charalampos Moschos

Published: 01 Jan, 2020

An efficient vaccine is vital for eliminating tuberculosis. The search has been going on for 100 years since the introduction of Bacillus Calmette-Guérin (BCG) vaccine. According to WHO, the new tuberculosis vaccines for adolescents and adults should have at least 50% efficacy against bacteriologically confirmed tuberculosis, and this efficacy should be sustained for at least 2 (and ideally 10) years. A new vaccine for tuberculosis was recently developed. It was tested in 3 African countries (South Africa, Zambia, Kenya) in adults 18-50 years old for efficacy, safety, and immunogenicity.

In particular, 3289 HIV negative adults with latent tuberculosis (QFT positive) received either 2 doses, one month apart, of M72/AS01E or placebo. They were followed up for 36 months. Efficacy was determined by the number of participants developing active tuberculosis at least one month after receiving the second dose (defined either microbiologically before starting treatment – primary end point-, or with different microbiological, molecular and clinical definitions -secondary end points-). Adverse events, potential immune-mediated diseases and, deaths were recorded. Immunogenicity was evaluated by measuring humoral and cell-mediated immune responses periodically until month 36.

The incidence of pulmonary tuberculosis was 0.3 cases per 100 person-years in the M72/AS01E group and 0.6 cases per 100 person-years in the placebo group. In total 13 new cases of active pulmonary tuberculosis developed in the vaccine group and 26 in the placebo group. The vaccine efficacy was 49.7%.
Injection-site reactions and influenza-like symptoms occurred more frequently in the M72/AS01E group than in the placebo group, but serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.

mmunogenicity was tested in the first 150 participants enrolled in Kenya and the first 150 enrolled in South Africa. Among participants in the M72/AS01E 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 with no evidence of waning.

An effective vaccine against tuberculosis is sorely needed if the END TB vision has any chance of succeeding. Several vaccines are in development and a vaccine that ‘protects’ TB infected individuals from developing active TB, like M72/AS01E, is an important tool in the fight against TB. Certain issues are still unclear though:

  1. The sample size in the study is small and it was conducted in high incidence countries (South Africa, Zambia, Kenya).
  2. The reported vaccine’s effectiveness is just barely within the limits defined by WHO
  3. There are no data about the vaccine’s effectiveness after three years
  4. There are no data about the vaccine’s effectiveness and safety in immunocompromised patients and PLWHIV.
  5. The vaccine needs to be tested in middle and low incidence countries
  6. Even if proven effective for longer periods in middle and low incidence countries, it will probably not replace the more effective strategy of LTBI treatment
  7. It will be extremely useful in selected subgroups:
    a. In high-risk patients who are more likely to default on LTBI treatment
    b. In high-risk patients, unwilling or unable to receive LTBI treatment (e.g. hepatitis, allergy or intolerance)
    c. In household contacts of patients with drug-resistant tuberculosis, especially contacts of XDR-TB patients, where no alternative exists at the moment.
  8. Pricing will be a vital issue in establishing a role for the vaccine, especially in the low income-high TB incidence countries where it is most needed.
Respiratory digests
Respiratory infections