M72/AS01E is a subunit candidate vaccine comprised of an immunogenic fusion protein (M72) derived from two Mycobacterium tuberculosis (M.tb) antigens (MTB32A and MTB39A), and the GlaxoSmithKline (GSK) proprietary adjuvant AS01E. AS01E is the same adjuvant used in Shingrix GSK vaccine, as well as in the new malaria vaccine RTS,S/AS01E.
The M72/AS01E vaccine candidate was developed by the pharmaceutical company GlaxoSmithKline, in partnership with AERAS. AERAS was a not for profit organization based in the US, aimed at supporting tuberculosis vaccine research, funded by the Bill and Melinda Gates foundation, the UK Department for International Development (DFID), and other organizations. Current efforts are being coordinated by the Bill & Melinda Gates Medical Research Institute.
WHO was not involved in the design or implementation of this trial.
The purpose of this study was to evaluate the safety, immunogenicity and protective efficacy of M72/AS01E vaccine against pulmonary TB, as compared to placebo in HIV negative adults with latent TB infection living in high TB burden countries (South Africa, Kenya and Zambia) and aged 18 - 50 years.
What is the trial design and the current status
This was a multicenter, double-blind, randomized, placebo-controlled trial participating 3573 HIV negative adults (18-50 years old) in Southern Africa (2873 from South Africa, 162 from Zambia, 538 from Kenya) who had evidence of M.tb infection at baseline (IGRA+) vaccinated with M72/AS01E or placebo on a 2 dose schedule administered at 1 month interval. The primary endpoint was the development of pulmonary TB. This was a case driven analysis, where analysis was triggered by the accrual of a certain number of pulmonary TB cases (1,2).
Can the vaccine cause unpleasant or dangerous reactions in people who have been vaccinated?
Individuals vaccinated with M72/AS01E experienced more local and flu-like general reactions than placebo recipients. There were no other concerning imbalances in safety events between the study groups.
The results showed that administering two-doses of M72/AS01E was successful in reducing the development of active TB disease with 50% efficacy (90% CI, 12 to 71) in HIV negative adults with latent Mycobacterium tuberculosis infection. A total of 39 participants contributed to the primary vaccine efficacy analysis during 3 years of follow up: 13 participants vaccinated with M72/AS01E developed pulmonary TB, as compared to 26 participants in the placebo group.
The exact mechanism of action of M72/AS01E is not known. Previous studies have showed that this vaccine induces an immune response characterized by the activation of interferon-gamma producing CD4+ T cells, and the production of antibodies. WHO strongly urges basic research to expand the current understanding of immune mechanisms of protection.
The study has demonstrated protection approximately during three years of study follow up. It is not currently known whether protection can extend for longer.
WHO has recently expressed a preference for a level of protection against tuberculosis in adults exceeding 50% efficacy. It will be important to determine whether the current vaccine also protects people who have not been infected with M.tb, across different geographical regions.
This has not been evaluated in the present study. However, a vaccine protective against pulmonary tuberculosis in adults, if used widely, has the potential to reduce drug resistant tuberculosis by reducing transmission and preventing the need for antibiotics; essential steps for curbing anti-microbial resistance. The role of this candidate vaccine in limiting the development and spread of drug-resistant forms of TB disease should be further evaluated.
WHO commends the efforts conducted in partnership between GSK, AERAS, study investigators, study participants, and countries in bringing this result forward. The results constitute an important scientific breakthrough, encouraging for the future role of new vaccines against TB. WHO with independent experts and formally constituted advisory committees will be reviewing data from this program, and consider evidence for policy.
In 2020, the Bill & Melinda Gates Medical Research Institute (Gates MRI) and the Bill & Melinda Gates Foundation (Gates Foundation) announced that GSK has outlicensed M72/AS01E to the Gates MRI, paving the way for continued development and potential use of the vaccine candidate in countries with high TB burdens.
WHO encourages the planning of accelerated progress towards a well-designed, Phase III program. Various priorities can be highlighted, including the need for a more precise estimation of vaccine efficacy, in different geographical settings, and further evaluation of safety. The effect of vaccination should also be characterized in people who do not have TB infection, in children, and in specific risk groups such as persons infected with HIV. This will require adequate vaccine production and financing. WHO calls on all relevant stakeholders including pharma, funders, governments, civil society, health care practitioners, policy makers and international agencies to work with a sense of urgency, in spirit of collaboration and a sense of responsibility towards public health, to bring forward the expedited validation of this product in the fight against tuberculosis.