Background:
Persons with tuberculosis (TB) who are deemed cured on completion of treatment remain at higher risk of recurrent disease. The TB vaccine candidate H56:IC31 has been shown to be safe and immunogenic in phase 1/2 studies, including in treated TB patients. Whether H56:IC31 can reduce the risk of recurrent TB is unknown.
Methods:
In a multicenter, double-blind, randomized, placebo-controlled, event-driven trial in South Africa and Tanzania, we enrolled participants aged 18-60 years, without HIV, who were sputum smear-negative upon completion of treatment for drug-sensitive pulmonary TB. Participants were randomly assigned (1:1) to receive two doses of H56:IC31 or placebo (56 days apart) and followed up for 1 year. The primary endpoint was recurrence of culture-confirmed pulmonary TB. Vaccine efficacy (VE) estimates with 95% confidence interval (95%CI) were derived from Cox proportional hazard models. Secondary endpoints included TB relapse or reinfection as differentiated by whole genome sequencing of paired sputum samples, safety, and immunogenicity.
Results:
831 participants (mean age 34.7 years; 27.6% female; 66.1% black African; 76% from South Africa) were enrolled; 415 received H56:IC31 and 416 placebo. In the primary analysis, recurrent TB was observed in 23 (12 relapse; 8 reinfection; 3 indeterminate) of 400 participants (5.8%) in the H56:IC31 group; and 14 (6 relapse; 7 reinfection; 1 indeterminate) of 406 participants (3.4%) in the placebo group. VE for recurrence was -73.8% (95%CI:-246.9 to 9.8%; P=0.10). VE for relapse was -116.1% (-522.2 to 16.3%; P=0.11) and for reinfection VE was -21.1% (-245.3 to 56.5%; P=0.71). Participants in the H56:IC31 group reported more mild-to-moderate local injection reactions than in the placebo group. No H56:IC31-related serious adverse events were observed. Participants receiving H56:IC31 mounted robust H56-specific CD4+ T cell responses and H56-specific humoral (serum IgG) responses.
Conclusions:
This is the first reported trial with a prevention of recurrent TB design. Vaccination with H56:IC31 upon treatment completion for pulmonary tuberculosis did not reduce the risk of recurrent tuberculosis. H56:IC31 was well-tolerated and immunogenic, but may have increased the risk of relapse by endogenous strains.
