1. In this randomized trial involving HIV-negative African adults with latent tuberculosis, vaccination with M72/AS01E provoked an immune response and offered 50% protection against progression to active pulmonary tuberculosis. The rates of serious adverse events, potential immune-mediated diseases, and death were similar between groups.
2. Participants in Kenya and South Africa displayed different patterns of CD4+ T-cell expression, suggesting that cellular differentiation may have been affected by infection-related, vaccine-induced, and ethnic-group factors.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Tuberculosis is the leading cause of death from a single pathogen and a top ten cause of death worldwide. M72/AS01E, an adjuvanted recombinant candidate vaccine, has previously been shown to be effective in preventing pulmonary tuberculosis in HIV-negative adults with latent M. tuberculosis infection in Kenya, South Africa, and Zambia. This study aimed to extend those results after an additional year of follow-up, finding that overall vaccine efficacy continued to hover around 50% with similar rates of adverse events and death between the treatment and placebo groups. All persons in the treatment group who were selected for inclusion in the immunogenicity cohort exhibited significantly increased frequencies of polypositive M72-specific CD4+ T cells and remained seropositive through month 36. However, there were no instances of progression to active pulmonary tuberculosis in this subgroup, meaning that no correlation between immune response and protection could be established. The persistence of these effects is encouraging, but the study findings need to be confirmed in larger, more diverse populations and across longer timeframes.
Relevant Reading: Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis
In-Depth [randomized controlled trial]: In this double-blind trial conducted in three African countries where tuberculosis is endemic, 3575 adults were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The efficacy cohort consisted of all participants who received at least one dose and were not found to have had active tuberculosis at any point prior to study enrollment, and the immunogenicity cohort consisted of the first 150 participants enrolled at each of two major centers. Using an unadjusted Cox regression model accounting for a mean follow-up of 2.7 years, the overall vaccine efficacy at month 36 was determined to be 49.7% (95% CI, 2.1 to 74.2) with 13 cases of active pulmonary tuberculosis in the treatment group (rate/100 person-years, 0.3; 90% CI, 0.2 to 0.5) and 26 cases in the placebo group (rate/100 person-years, 0.6; 90% CI, 0.4 to 0.8). Adjusting for several factors including country, sex, age, and previous bacille Calmette-Guérin vaccination yielded nearly identical results. Participants in the treatment group exhibited a substantial increase in both anti-M72 IgG antibody concentration and frequency of polypositive M72-specific CD4+ T-cells with predominant expression of interferon-γ, interleukin-2, and TNF-α. No CD8+ T-cell responses were detected in either group. Overall mortality was lower in the treatment group (relative risk, 0.68; 95% CI, 0.36 to 1.26; P=0.24), and only one serious adverse event related to the trial regimen occurred in each group, with onset on the day of administration.
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