An innovative clinical trial conducted by the University of Cape Town-based SA Tuberculosis Vaccine Initiative and the Desmond Tutu HIV Foundation provides encouraging new evidence that TB vaccines could prevent sustained infections in high-risk adolescents.
According to the World Health Organisation (WHO), about one-quarter of the world's population has latent TB infection, which means people have been infected by TB bacteria but are not ill with the disease and cannot transmit the disease. People infected with TB bacteria have a lifetime risk of falling ill with TB of 10%. In a prevention-of-infection phase 2 trial conducted in Worcester and Cape Town, South Africa, re-vaccination with the Bacille Calmette-Guerin (BCG) vaccine significantly reduced sustained TB infections in adolescents.
An experimental vaccine candidate, H4:IC31, also appeared to reduce sustained infections, although not at statistically significant levels. However, the trend observed for H4:IC31 is the first time a subunit vaccine has shown any indication of ability to protect against TB infection or disease in humans. TB infections that developed during the study were measured using a QuantiFERON®-TB Gold in Tube (QFT-GIT) test, a commercially available blood test that helps diagnose TB infections. In the trial, individuals who tested negative for QFT-GIT were considered to not have TB infection. The trial measured the rate by which individuals converted to QFT-GIT positive, interpreted as evidence of TB infection. Those individuals who tested QFT-GIT positive consecutively over 6 months were considered to have a sustained infection.
H4:IC31 is a sub-unit TB vaccine candidate being developed jointly by Aeras and Sanofi Pasteur and the Statens Serum Institute. BCG is the only licensed tuberculosis vaccine available globally.
The clinical trial was conducted at SATVI and at the Emavundleni Research Centre (part of the Desmond Tutu HIV Centre). The trial was funded by Sanofi Pasteur, the UK’s department for international development, and Aeras. The study was approved by the Medicines Control Council of South Africa and the independent ethics committee of the University of Cape Town.
The study involved 990 HIV-negative, healthy adolescents (12 to 17 years of age) who had previously been vaccinated as infants with BCG. All participants were randomized evenly into three study arms: placebo, H4:IC31, or BCG revaccination. All participants were screened to ensure they were not infected with Mycobacterium tuberculosis (Mtb) prior to vaccination in the study.
The data showed that both vaccines appeared to be safe and produced an immune response in the adolescents studied. No vaccine-related serious adverse events were reported in the study, and the most common vaccine-related adverse event was injection site swelling in BCG revaccinated participants, typical for BCG vaccination.
For the primary efficacy outcome, 134 participants tested positive for an initial Mtb infection as measured by QFT-GIT conversion from negative to positive. When compared to the placebo, neither vaccine prevented initial Mtb infection (QFT-GIT conversion). For the secondary efficacy outcome, 82 participants exhibited a sustained QFT-GIT conversion which remained positive for at least 6 months.
In the BCG revaccination arm, the vaccine efficacy for preventing a sustained infection was 45.4% and was statistically significant. In the H4:IC31 arm, vaccine efficacy was 30.5%, but did not meet rigorous criteria for statistical significance.
This convincing BCG efficacy signal provides impetus for trials of BCG revaccination for prevention of TB disease in adolescents without Mtb infection, which would be needed to confirm direct clinical benefit of the prevention-of-infection approach. The modest efficacy effect of H4:IC31 encourages further testing of next generation subunit TB vaccines.
Dr Mark Hatherill, director of the SATVI and the study’s principal investigator, said: “We are very pleased to publish the results of the first randomised, placebo-controlled prevention-of-infection trial for TB, which showed that vaccination may reduce the rate of sustained TB infection in a high-transmission setting. While neither vaccine proved to be statistically significant in preventing an initial TB infection, we are extremely encouraged by the efficacy findings against sustained TB infections. We believe the results from this novel trial design will provide significant scientific benefit to the field in understanding protection against TB infection, and based on this positive signal, we look forward to testing the potential of such vaccines to protect against TB disease among uninfected adolescents in a larger, more traditional prevention-of-disease clinical trial.”
Dr Tom Scriba, deputy director immunology of SATVI, said “We are excited that this result provides an opportunity to identify the immune response that protects against sustained TB infection. This advance would accelerate rational development of new TB vaccines.”
Dr Linda-Gail Bekker, a lead investigator for the trial, the COO at the Desmond Tutu HIV Foundation and president of the International AIDS Society, said: “We would like to thank all the study participants and their families for participating in this novel clinical trial. We believe the results are important and warrant further investigation into other subunit vaccines and a re-evaluation of BCG revaccination as a potential strategy to prevent TB in high-incidence countries. An effective TB vaccine remains an urgent global goal.”
Dr Jacqueline Shea, CEO at Aeras, said: “These results highlight the importance of investing in new approaches to fighting the leading infectious disease killer and to evaluating new concepts in clinical trials. Further, the collaborative effort established between industry leaders, non-profits and clinical sites during this trial showed how powerful combining such forces can be for developing new interventions against a global health threat. The BCG results are important findings with significant public health implications, especially with the rise of drug-resistant strains, that could lead to saving millions of lives. Likewise, the novel prevention-of-infection trial design can be used to inform clinical development of new vaccine candidates before entry into large-scale prevention-of-disease efficacy trials. We are very grateful to the trial participants and our partners and funders who enabled the conduct of this trial.”
Background: Recent Mycobacterium tuberculosis infection confers a predisposition to the development of tuberculosis disease, the leading killer among global infectious diseases. H4:IC31, a candidate subunit vaccine, has shown protection against tuberculosis disease in preclinical models, and observational studies have indicated that primary bacille Calmette–Guérin (BCG) vaccination may offer partial protection against infection.
Methods: In this phase 2 trial, we randomly assigned 990 adolescents in a high-risk setting who had undergone neonatal BCG vaccination to receive the H4:IC31 vaccine, BCG revaccination, or placebo. All the participants had negative results on testing for M. tuberculosis infection on the QuantiFERON-TB Gold In-tube assay (QFT) and for the human immunodeficiency virus. The primary outcomes were safety and acquisition of M. tuberculosis infection, as defined by initial conversion on QFT that was performed every 6 months during a 2-year period. Secondary outcomes were immunogenicity and sustained QFT conversion to a positive test without reversion to negative status at 3 months and 6 months after conversion. Estimates of vaccine efficacy are based on hazard ratios from Cox regression models and compare each vaccine with placebo.
Results: Both the BCG and H4:IC31 vaccines were immunogenic. QFT conversion occurred in 44 of 308 participants (14.3%) in the H4:IC31 group and in 41 of 312 participants (13.1%) in the BCG group, as compared with 49 of 310 participants (15.8%) in the placebo group; the rate of sustained conversion was 8.1% in the H4:IC31 group and 6.7% in the BCG group, as compared with 11.6% in the placebo group. Neither the H4:IC31 vaccine nor the BCG vaccine prevented initial QFT conversion, with efficacy point estimates of 9.4% (P=0.63) and 20.1% (P=0.29), respectively. However, the BCG vaccine reduced the rate of sustained QFT conversion, with an efficacy of 45.4% (P=0.03); the efficacy of the H4:IC31 vaccine was 30.5% (P=0.16). There were no clinically significant between-group differences in the rates of serious adverse events, although mild-to-moderate injection-site reactions were more common with BCG revaccination.
Conclusions: In this trial, the rate of sustained QFT conversion, which may reflect sustained M. tuberculosisinfection, was reduced by vaccination in a high-transmission setting. This finding may inform clinical development of new vaccine candidates.
Elisa Nemes, Hennie Geldenhuys, Virginie Rozot, Kathryn T. Rutkowski, Frances Ratangee, Nicole Bilek, Simbarashe Mabwe, Lebohang Makhethe, Mzwandile Erasmus, Asma Toefy, Humphrey Mulenga, Willem A Hanekom, Steven G Self, Linda-Gail Bekker, Robert Ryall, Sanjay Gurunathan, Carlos A DiazGranados, Peter Andersen, Ingrid Kromann, Thomas Evans, Ruth D Ellis, Bernard Landry, David A Hokey, Robert Hopkins, Ann M Ginsberg, Thomas J Scriba, Mark Hatherill