Vaccine prevents active tuberculosis in adults with latent tuberculosis (NNT = 333 over 3 years)

Reference

Tait DR, Hatherill M, van der Meeren O, et al. Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. N Engl J Med 2019;381(25):2429-2439.

Synopsis

M. tuberculosis infection remains an important public health threat, particularly in low-income countries. In this study, set in Kenya, South Africa, and Zambia, 3289 adults aged 18 to 50 years who were HIV-negative, had a positive interferon-gamma release result for infection with M. tuberculosis, and no signs of active disease were randomized to receive either 2 doses of the M72/AS01E vaccine given 1 month apart or matching placebo. All but 2 patients randomized to the vaccine group received the first injection, but 243 failed to get the second injection. Groups were balanced at the beginning of the study, and approximately two-thirds of participants were 30 years or younger. The primary analysis included only the patients who received both injections, a per-protocol analysis that inflates benefit compared with the preferred intention-to-treat analysis. The authors describe a 50% vaccine efficacy rate, which is, of course, a relative measure and also inflates the apparent benefit. More clinically meaningful are the absolute risks of developing TB, which were 0.3% in the vaccine group and 0.6% in the placebo group during the 3 years after immunization (P < .05; NNT = 333 to prevent one case of active TB over 3 years). There was odd clustering by age, with 3 cases in the vaccine group and 16 in the placebo group among patients 25 years or younger, 6 vs 2 among those 26 to 30 years, and 4 vs 8 among patients older than 30 years. Thus, using a cutoff of 25 years, the vaccine appears to be highly effective in young patients and totally ineffective in the older group, but using a cutoff of 30 years, the efficacy is similar between older and younger patients. Analyzing age as a continuous variable, though, found no association with vaccine effectiveness. The vaccine was generally safe, and there was no significant difference in mortality between groups. Immunogenicity persisted throughout the 3-year study in the subset of patients in whom it was studied. The study was not powered to detect an effect on mortality.