A candidate tuberculosis vaccine significantly reduced the incidence of pulmonary tuberculosis in HIV-negative adults who were already infected with latent TB at the time of vaccination, according to results from an ongoing clinical trial in in Kenya, South Africa and Zambia.
The primary results of an ongoing phase IIb clinical trial testing the candidate tuberculosis vaccine M72/AS01E1 have been published. This analysis shows that M72/AS01E significantly reduced the incidence of pulmonary tuberculosis disease in HIV-negative adults who were already infected with latent TB at the time of vaccination. The results demonstrate an overall vaccine efficacy of 54%, with varied response rates observed in different demographic sub-groups. The candidate vaccine had an acceptable safety and reactogenicity profile.
The South African Tuberculosis Vaccine Initiative (SATVI) and the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), tuberculosis research groups based in the Institute of Infectious Disease & Molecular Medicine at the University of Cape Town, are two of 11 sites in Kenya, South Africa and Zambia where the study is conducted. The study is sponsored by the global healthcare company GlaxoSmithKline (GSK), and conducted in partnership with Aeras, a non-profit organization dedicated to developing vaccines against tuberculosis.
Tuberculosis is the leading cause of death through infectious disease worldwide and represents a significant public health threat with 1.6m attributed deaths in 2016 globally. In South Africa, the estimated incidence of tuberculosis is 781 per 100,000 of the population. The World Health Organisation estimates that one-quarter of the global population has latent tuberculosis, with increasing prevalence of multi-drug resistant strains. Currently, there is no available tuberculosis vaccine with proven, consistent efficacy in adult populations.
“These results are a major advance for TB vaccine development, showing for the first time that a protein sub-unit vaccine can prevent progression to active TB disease in people who are already infected with latent TB at the time of vaccination,” says Professor Mark Hatherill. “We are thrilled that a new generation TB vaccine candidate can prevent progression to active TB disease. This study lays the foundation for the next step, which is to determine what this protective immune response looks like so that we can improve TB vaccines even further,” said Associate Professor Thomas Scriba.
Professor Robert J Wilkinson of CIDRI-Africa, Imperial College and the Francis Crick Institute London commented: ‘’We are pleased to have had a large part in the conduct and analysis of this study. The results are intriguing and, overall, highly encouraging. A major task now will be to analyse samples collected from the trial to look for clues how we might do even better. Our previous experience and the combination of Crick and the Wellcome Centre in Cape Town uniquely positions us to play a significant role in this effort, at the same time as contributing to the development of scientific careers in Africa.’
The study assesses the safety and efficacy of M72/AS01E, in adults with latent tuberculosis infection, against development of pulmonary tuberculosis disease. The ongoing trial is conducted in tuberculosis-endemic regions in Kenya, South Africa and Zambia and involves 3,573 HIV-negative adults. For this analysis, participants who received two doses of either M72/AS01E or placebo 30 days apart have been followed for at least 2 years to detect evidence of pulmonary tuberculosis disease. Ten participants who received the vaccine developed active pulmonary tuberculosis compared to 22 participants in the placebo group.
The study is still ongoing and a final analysis including all efficacy, safety, reactogenicity and immunogenicity data will be performed in 2019 after all participants have completed three years of follow up.
The study is sponsored by GSK and conducted in partnership with Aeras. Funders include the Bill & Melinda Gates Foundation, the UK’s Department for International Development, the directorate general for international cooperation in the Netherlands, and the Australian Agency for International Development.
Background: A vaccine to interrupt the transmission of tuberculosis is needed.
Methods: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)–negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette–Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both.
Results: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.
Conclusions: M72/AS01E provided 54.0% protection for M. tuberculosis–infected adults against active pulmonary tuberculosis disease, without evident safety concerns
Olivier Van Der Meeren, Mark Hatherill, Videlis Nduba, Robert J Wilkinson, Monde Muyoyeta, Elana Van Brakel, Helen M Ayles, German Henostroza, Friedrich Thienemann, Thomas J Scriba, Andreas Diacon, Gretta L Blatner, Marie-Ange Demoitié, Michele Tameris, Mookho Malahleha, James C Innes, Elizabeth Hellström, Neil Martinson, Tina Singh, Elaine J Akite, Aisha Khatoon Azam, Anne Bollaerts, Ann M Ginsberg, Thomas G Evans, Paul Gillard, Dereck R Tait