A PHASE IIb clinical trial evaluating the tuberculosis vaccine H56:IC31 has found no evidence that it reduces the risk of recurrent disease in individuals who have completed treatment for pulmonary tuberculosis.
The study was conducted across six sites in South Africa and Tanzania, enrolling 831 participants aged 18–60 years without HIV. Participants who had completed at least 22 weeks of treatment for drug-susceptible pulmonary tuberculosis were randomly assigned in a 1:1 ratio to receive two intramuscular doses of either H56:IC31 or placebo, 56 days apart. Follow-up continued for 1 year after the second dose, with regular assessments for tuberculosis symptoms. Recurrence was confirmed by sputum culture, and whole-genome sequencing was used to distinguish between relapse (same strain) and reinfection (different strain). The primary endpoint was culture-confirmed recurrence between days 70 and 421, with vaccine efficacy calculated using Cox proportional hazards models.
Among the 400 participants who received H56:IC31 in the modified intention-to-treat analysis, 23 experienced tuberculosis recurrence (12 relapses, eight reinfections, and three indeterminate cases), compared with 14 cases in the 406 placebo recipients (six relapses, seven reinfections, and one indeterminate). Vaccine efficacy against overall recurrence was –73.8% (95% CI: -246.9–9.8; p=0.10), with efficacy against relapse at –116.1% (–522.2–16.3; p=0.11) and reinfection at –21.1% (–245.3–56.5; p=0.71), indicating no protective effect. However, vaccine recipients exhibited significantly higher frequencies of H56-specific CD4 T cells (0.35% [IQR 0.19–0.57] vs. 0.11% [0.09–0.23]; p<0.0001) and elevated IgG responses (6.84 [IQR 1.64–32.8] vs. 1.94 [1.05–3.86]; p<0.0001). Mild-to-moderate injection site reactions were more common in vaccine recipients (40% vs. 19%). No vaccine-related serious adverse events were reported, but mortality was slightly higher in the placebo group (six deaths vs. two in the vaccine group).
While H56:IC31 was well tolerated and generated strong immune responses, it did not prevent tuberculosis recurrence and may have increased the risk of relapse. Further research is needed to understand the vaccine’s effect on tuberculosis pathogenesis and whether alternative strategies could improve outcomes.
Ada Enesco, EMJ
Reference
Borges AH et al. Immunogenicity, safety, and efficacy of the vaccine H56:IC31 in reducing the rate of tuberculosis disease recurrence in HIV-negative adults successfully treated for drug-susceptible pulmonary tuberculosis: a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Infect Dis. 2025;DOI:10.1016/S1473-3099(24)00814-4.
