Patients who have successfully completed tuberculosis treatment still face a high risk of relapse, making the development of vaccines to prevent recurrent pulmonary tuberculosis an important direction in TB prevention efforts. At the recently concluded 31st Conference on Retroviruses and Opportunistic Infections (CROI 2024), a study presented as a late-breaking abstract (Abstract Number: 210) revealed that the novel tuberculosis vaccine H56:IC31, while not reducing the rate of TB relapse, enhanced both humoral and cellular immune responses in recipients. This marks the first clinical multicenter, randomized controlled trial (RCT) reported on the use of a TB vaccine for the prevention of relapse. The Infectious Disease Frontier has invited Dr. Shuihua Lu and his team from The Third People’s Hospital of Shenzhen to introduce and comment on this study as follows.
Study Overview
Abstract Number: 210
Title: Efficacy, Safety, and Immunogenicity of the H56:IC31 Vaccine for Prevention of Recurrent TB
Background:
Patients treated for tuberculosis (TB) are considered cured after completing their treatment, yet they remain at a high risk of disease relapse. The TB candidate vaccine H56:IC31 has demonstrated safety and immunogenicity in phase 1/2 studies, including among patients treated for TB. Whether H56:IC31 can reduce the risk of TB relapse remains unclear.
Method:
A multicenter, double-blind, randomized, placebo-controlled, event-driven trial was conducted in South Africa and Tanzania, enrolling participants aged 18-60 years who were HIV-negative and had a negative sputum smear after completing treatment for drug-sensitive pulmonary TB. Participants were randomly assigned (1:1) to receive two doses of H56:IC31 or a placebo (56 days apart) and followed for one year. The primary endpoint was culture-confirmed pulmonary TB relapse. Vaccine efficacy (VE) estimates, with 95% confidence intervals (CI), were derived from the Cox proportional hazards model. Secondary endpoints included TB relapse or reinfection (distinguished by whole-genome sequencing of paired sputum samples), safety, and immunogenicity.
Results:
The study enrolled 831 participants (mean age 34.7 years, 27.6% female, 66.1% Black African, 76% from South Africa), with 415 receiving H56:IC31 and 416 receiving a placebo. In preliminary analyses, among 400 participants in the H56:IC31 group, 23 (5.8%) observed TB relapse (12 relapses, 8 reinfections, 3 uncertain), compared to 14 (3.4%) in the placebo group of 406 participants (6 relapses, 7 reinfections, 1 uncertain). The VE for preventing recurrence was -73.8% (95% CI: -246.9 to 9.8%, P=0.10). The VE for preventing relapse was -116.1% (-522.2 to 16.3%, P=0.11), and the VE for preventing reinfection was -21.1% (-245.3 to 56.5%, P=0.71).
Compared to the placebo group, participants in the H56:IC31 group reported more mild to moderate local injection reactions. No serious adverse events related to H56:IC31 were observed. Participants who received H56:IC31 produced strong H56-specific CD4+ T cell responses and H56-specific humoral (serum IgG) responses.
Conclusion:
This is the first trial reported to be designed for the prevention of recurrent tuberculosis. Vaccination with H56:IC31 after the completion of pulmonary tuberculosis treatment did not reduce the risk of TB relapse. H56:IC31 was well-tolerated and immunogenic, but may have increased the risk of relapse with endogenous strains.
Study Commentary:
Mycobacterium tuberculosis remains the leading cause of death from a single infectious agent. Bacille Calmette-Guérin (BCG) is currently the only TB prevention vaccine, targeted at infants and newborns, with a global coverage rate of about 90%. Despite this, one person dies from TB every 20 seconds. The effectiveness of BCG ranges from 0% to 80%, decreasing with age, and it cannot prevent most adult TB infections and disease, nor can it prevent disease in those with latent infections or TB relapse. Thus, a major trend in TB research in recent years has been the exploration of new TB vaccines that are safe and effective for all ages, both infected and uninfected with Mtb.
Research on new TB vaccines has mainly focused on three types: vaccines for primary prevention as a substitute for BCG, booster vaccines after BCG primary immunization, and therapeutic vaccines for those with latent infections. Currently, 16 new TB vaccines are undergoing clinical trials, including attenuated live mycobacterial vaccines (e.g., MTBVAC), inactivated mycobacterial vaccines or extracts (e.g., Mycobacterium Vaccae, MIP), viral vector vaccines (e.g., MVA85A, ChAdOx1 85A), subunit/adjuvant vaccines (e.g., M72/AS01E, AEC/BC02), and mRNA vaccines (e.g., BNT164), but to date, no new TB vaccine has been successfully launched.
The H56:IC31 subunit vaccine is a novel multistage vaccine designed for different stages of infection, composed of the Mtb secreted antigens Ag85B and ESAT-6, the Mtb latency-associated antigen Rv2660c, and the IC31 adjuvant, enhancing both cellular and humoral immune responses. The H56:IC31 vaccine has been proven in phase I/II clinical studies to be safe and immunogenic in both Mtb-infected and uninfected individuals, inducing a durable antigen-specific Th1 response.
Patients considered cured after completing TB treatment still face a high risk of relapse. The H56:IC31 vaccine targets this population in a multicenter, double-blind, randomized, placebo-controlled, event-driven clinical trial conducted in South Africa and Tanzania. The trial enrolled 831 participants aged 18-60 years, HIV-negative, who completed treatment for drug-sensitive pulmonary TB with a negative sputum smear. Participants were randomly assigned 1:1 to receive two doses of H56:IC31 or placebo, followed for one year. Among 400 participants in the H56:IC31 group, 23 (5.8%) observed TB relapse (12 relapses, 8 reinfections, 3 uncertain), compared to 14 (3.4%) in the placebo group of 406 participants (6 relapses, 7 reinfections, 1 uncertain). Compared to the placebo group, the H56:IC31 group reported more mild to moderate local injection reactions, with no observed related serious adverse reactions. Notably, recipients of H56:IC31 generated strong H56-specific CD4+T cell responses and H56-specific humoral immune responses (serum IgG).
In summary, the proportion of TB patients successfully treated is a key indicator for monitoring the progress of the End TB strategy, and developing vaccines to prevent recurrent pulmonary TB has become an important direction in TB prevention. Although the H56:IC31 vaccine did not reduce the rate of TB relapse, it enhanced the recipients’ humoral and cellular immune responses, bringing hope towards achieving the goal of developing a vaccine to prevent recurrent pulmonary TB.
Dr. Shuihua Lu
Deputy Director of the National Clinical Research Center for Infectious Diseases
Director of the Pulmonary Medicine Department, The Third People’s Hospital of Shenzhen
Xiaomin Wang
Shenzhen National Clinical Research Center for Infectious Diseases
