Publication of primary results in the New England Journal of Medicine shows positive impact of innovative vaccine technology in clinical trial conducted in tuberculosis endemic regions.
Today, GSK and Aeras reported that GSK’s M72/AS01E candidate vaccine significantly reduced the incidence of pulmonary tuberculosis disease in HIV-negative adults with latent tuberculosis infection in an ongoing phase IIb clinical trial testing. These primary results published in the New England Journal of Medicine after two years of trial 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.
Tuberculosis is the leading cause of death through infectious disease worldwide and represents a significant public health threat with 1.6 million attributed deaths in 2017. It is estimated that one-quarter of the global population has latent tuberculosis infection, of whom approximately 10% will develop active pulmonary tuberculosis disease. Currently, multi-drug resistant strains of tuberculosis are emerging globally, and the only currently available vaccine against tuberculosis, BCG, does not provide proven and consistent protection in adults in tuberculosis endemic countries. Without a more effective vaccine, it will not be possible to achieve the WHO target of decreasing the number of new cases by 90% and the number of tuberculosis deaths by 95% between 2015 and 2035.
Dr Emmanuel Hanon, Senior Vice-President and Head of R&D, Global Vaccines GSK, said: “These initial findings represent a significant innovation in the development of a new and much-needed vaccine and advance the scientific understanding of tuberculosis. This scientific breakthrough – one of the very few in tuberculosis vaccine development for almost 100 years – has been made possible by our strategic partnership with Aeras, in which GSK is providing the innovation expertise and technology platforms, such as the proprietary AS01 adjuvant.”
The study assesses the safety and efficacy of M72/AS01E protecting adults with latent tuberculosis infection against developing pulmonary tuberculosis disease. The ongoing trial is conducted in tuberculosis endemic regions (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 up for at least 2 years to detect evidence of pulmonary tuberculosis disease. In the vaccine group, 10 participants developed active pulmonary tuberculosis compared to 22 participants in the placebo group.
Jacqui Shea, Chief Executive Officer of Aeras, which contributed to the partnership their decades long experience in tuberculosis vaccine clinical development, clinical operations capabilities and strong links with African clinical sites and patient communities, said: “This ground-breaking study shows – for the first time – that a subunit vaccine can significantly reduce the incidence of pulmonary tuberculosis in healthy, HIV-negative adults with latent tuberculosis infection, and that more effective vaccines against tuberculosis are achievable. Given the overwhelming public health need, the importance of these promising results, which need to be confirmed through additional clinical research, cannot be overstated. An effective vaccine, able to reduce transmission, would be by far the most impactful new intervention to end the global tuberculosis epidemic”.
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.
About the study
The study is sponsored by GSK and conducted in partnership with Aeras. Funders of Aeras for this study are the Bill & Melinda Gates Foundation, the United Kingdom’s Department for International Development, the Directorate General for International Cooperation in the Netherlands, and the Australian Agency for International Development.
This study is a Phase IIb, multicentre, randomized (ratio 1:1), double-blind, placebo-controlled study with 2 groups: M72/AS01E or placebo. The study is conducted in tuberculosis endemic regions, at 11 sites in South-Africa, Zambia and Kenya. (www.clinicaltrials.gov NCT01755598)
The primary objective of the study is to investigate if two doses of the M72/AS01E candidate vaccine can prevent adults with latent Mycobacterium tuberculosis infection from developing tuberculosis disease, compared to people who receive placebo. The study also evaluates the safety, reactogenicity and immunogenicity of the M72/AS01E candidate vaccine.
The data just published in the New England Journal of Medicine (DOI: NEJMdo005415) are initial findings, in which variable efficacy is observed in some sub-populations. However, these sub-group analyses include small numbers of people and therefore will need to be confirmed. Final analysis of these subgroups will be conducted after the study concludes in 2019, at which time there may be more data points to provide greater insight into the initially observed variability.
Nearly all participants (99%) in the study consented to enter into a biobanking study sponsored by Aeras. The samples collected during this study will allow researchers to further investigate the potential vaccine-induced mechanisms of protection against tuberculosis and attempt to identify markers that indicate those at high risk of developing tuberculosis disease. (www.clinicaltrials.gov NCT02097095).
About the candidate vaccine
GSK’s M72/AS01E candidate vaccine contains the M72 recombinant fusion protein derived from two Mycobacterium tuberculosis antigens (Mtb32A and Mtb39A), combined with the Adjuvant System AS01, which is also a component of the GSK’s RTS,S/AS01 and Shingrix vaccines.
Primary results showed M72/AS01E to have an acceptable safety and reactogenicity profile. Solicited and unsolicited adverse events within 7 days post-injection were more frequent among M72/AS01E recipients (91.2%) than placebo recipients (68.9%), the difference attributed mainly to injection site reactions and flu-like symptoms. Serious adverse events, potential immune-mediated diseases and deaths all occurred with similar low frequencies between groups. The fatalities encountered amongst the participants in this study were unrelated to the administration of the candidate vaccine or placebo.
One-quarter of the global population is estimated has latent tuberculosis, and tuberculosis is the leading infectious cause of deathworldwide,. There were an estimated 10 million new tuberculosis cases and 1.6 million deaths attributed to tuberculosis in 2017. After the initial infection with Mtb, the disease – if untreated – often progresses to involve large parts of the lung causing pulmonary tuberculosis which is responsible for the majority of the fatalities caused by tuberculosis. An effective vaccine against tuberculosis would have a marked impact on tuberculosis’ control, including drug-resistant tuberculosis, through interruption of transmission,, and it would help achieve the WHO target of ending the tuberculosis epidemic by 2035.
Aeras is a non-profit organization advancing the development of new tuberculosis vaccines for the world in partnership with other biotech, pharmaceutical and academic organizations. Aeras is primarily funded by The Bill & Melinda Gates Foundation, the UK Department for International Development (DFID), and other parties committed to ending the tuberculosis epidemic. Aeras also receives support from the U.S. government and through partnerships and collaborations with universities and pharmaceutical companies around the world. Aeras is headquartered in Rockville, Maryland (USA), with a clinical development and operations office in Cape Town, South Africa. For more information, please visit www.aeras.org.
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Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D 'Principal risks and uncertainties' in the company's Annual Report on Form 20-F for 2017.
 The GSK proprietary AS01 adjuvant system contains QS-21 Stimulon® adjuvant licensed from Antigenics LLC, a wholly owned subsidiary of Agenus Inc. (NASDAQ: AGEN), MPL and liposomes
 WHO, Latent tuberculosis infection: updated and consolidated guidelines for programmatic management, 2018
 Sites in South Africa: SATVI, Task, Setshaba, Aurum-Klerksdorp, Aurum-Tembisa, PHRU, CIDRI, and Be Part; sites in Zambia: CIDRZ and Zambart; and sites in Kenya: KEMRI.
 Houben RM, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Reestimation
Using Mathematical Modelling. PLoS Med 2016;13:e1002152
 World Health Organization. Global Tuberculosis Report 2018 (http://www.who.int/tb/publications/global_report/en/)
 Dheda K, Gumbo T, Maartens G, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 2017; 5:291-360
 Harris RC, Sumner T, Knight GM, White RG. Systematic review of mathematical models exploring the epidemiological impact of future TB vaccines. Hum Vaccin Immunother 2016;12:2813-32