Final results from M72/AS01E candidate vaccine against tuberculosis (TB) announced at the TB Science Conference, Hyderabad, India. Scientists from the South African Tuberculosis Vaccine Initiative (SATVI) and the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) at the University of Cape Town, GlaxoSmithKline (GSK), and the International AIDS Vaccine Initiative (IAVI) have announced the final results of a large trial of the safety, immunogenicity and efficacy of the M72/AS01E candidate TB vaccine.
M72/AS01E vaccination of HIV-negative adults with latent TB infection reduced the incidence of pulmonary TB by 50% over a three-year period. Background TB is the leading cause of infectious disease mortality. According to the World Health Organisation, 10m people fell ill with TB and 1.5m people died from TB in 2018.
Development of a new and effective vaccine to prevent progression to pulmonary TB in adults with quiescent or ‘latent’ infection with the Mycobacterium tuberculosis bacterium is key to interruption of TB transmission and control of the global TB epidemic.
The primary objective of this study, which was conducted at 11 sites in Kenya, South Africa and Zambia, including SATVI and CIDRI-Africa at the University of Cape Town, was to evaluate the efficacy of the M72/AS01E candidate vaccine against pulmonary TB.
A total of 3,575 HIV-negative, latently infected adults aged 18 to 50 years received two doses of either M72/AS01E or an inactive placebo, and were followed for three years for evidence of pulmonary TB. 13 participants in the vaccine group and 26 participants in the placebo group developed pulmonary TB, with overall vaccine efficacy of 50%.
The results of this final analysis are consistent with results of the primary analysis after two years of follow-up. These results confirmed the previously reported acceptable safety profile of M72/AS01E and also showed that the vaccine induced immune responses that persisted for three years.
The trial was sponsored by GSK and conducted in partnership with IAVI with funding from the Bill and Melinda Gates Foundation, the UK Department for International Development, the government of the Netherlands directorate-general for international cooperation, and Australian AID.
Professor Mark Hatherill, SATVI director said “These are game-changing results. If we can offer latently infected adults durable protection against pulmonary TB disease we may be able to interrupt the cycle of TB transmission”. Professor Tom Scriba, SATVI deputy director, immunology said “This ground-breaking study demonstrates that a vaccine can provide long-term protection against lung TB. We are also now able to decipher exactly how the immune response can protect humans against TB”. About SATVI The South African Tuberculosis Vaccine Initiative (SATVI) is a TB research group based at the faculty of health sciences of the University of Cape Town. SATVI is regarded as a worldwide leader in TB vaccine research and has conducted 28 Phase I–IV trials of 9 different TB vaccine candidates since 2005. SATVI’s research focus is understanding the risk for, and protection against, M. tuberculosis infection and disease, in order to develop more effective vaccines and preventive strategies for global impact on the TB epidemic.
The results were described as “ground-breaking” and experts hope they may mark a turning point in the battle against the disease, reports The Daily Telegraph. The BCG is the only the vaccine currently available for TB and was developed more than 100 years ago. Although it protects children from certain types of the disease, the jab does not protect adults or adolescents.
“This is an exciting development towards a vaccine, which could effectively prevent tuberculosis infection and disease,” Dr Tim Wingfield, a TB expert at the Liverpool School of Tropical Medicine who was not involved in the trial, is quoted in the report as saying. But he said that more trials are needed to confirm the initial findings.
“The next vital steps will be to evaluate the impact and durability of the vaccine in preventing tuberculosis disease in real-world, rather than clinical trial, settings,” he said. This needs to include other regions of the world and different sub-populations, particularly those who are malnourished or extremely poor, Wingfield added.
Ann Ginsberg from IAVI called the trial results “ground-breaking”. Peter Kim, from the National Institutes of Health in the US added: “The results are truly astonishing worthy of applause and celebration. An effective vaccine against TB is exactly the type of game changer we need to end TB epidemic once and for all.”
Background: Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity.
Methods: From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo.
Results: A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.
Conclusions: Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years.
Dereck R Tait, Mark Hatherill, Olivier Van Der Meeren, Ann M Ginsberg, Elana Van Brakel, Bruno Salaun, Thomas J Scriba, Elaine J Akite, Helen M Ayles, Anne Bollaerts, Marie-Ange Demoitié, Andreas Diacon, Thomas G Evans, Paul Gillard, Elizabeth Hellström, James C Innes, Maria Lempicki, Mookho Malahleha, Neil Martinson, Doris Mesia Vela, Monde Muyoyeta, Videlis Nduba, Thierry G Pascal, Michele Tameris, Friedrich Thienemann, Robert J Wilkinson, François Roman
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa1909953"]New England Journal of Medicine abstract[/link]
[link url="https://www.telegraph.co.uk/global-health/science-and-disease/hopes-rise-new-tb-vaccine-early-trial-shows-astonishing-results/?WT.mc_id=e_DM1130078&WT.tsrc=email&etype=Edi_GHS_New_Weekly&utmsource=email&utm_medium=Edi_GHS_New_Weekly20191031&utm_campaign=DM1130078"]The Daily Telegraph report[/link]