Q&A on the investigational vaccine candidate M72/AS01E

M72/AS01E is a subunit 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 is being developed by the pharmaceutical company GlaxoSmithKline, in partnership with AERAS. AERAS is 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. 

WHO was not involved in the design or implementation of this trial.

The purpose of this ongoing study is 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. The study remains ongoing and the final analysis is planned in 2019.

• 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 Mtb 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. While the primary analysis has now been released1 , the study is ongoing, with a final descriptive analysis planned for release in 2019.
• 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 safety imbalances between the study groups. The study is still blinded at the individual level. Full unblinding of the safety data is expected during the final analysis.
• Efficacy results
  
  The results showed that administering two-doses of M72/AS01E was successful in reducing the development of active TB disease with 54% efficacy (90% CI, 13.9 to 75.4; 95% CI, 2.9 to 78.2; P = 0.04) in HIV negative adults with latent Mycobacterium tuberculosis infection. A total of 32 participants contributed to the primary vaccine efficacy analysis during 2 years of follow up: 10 participants vaccinated with M72/AS01E developed pulmonary TB, as compared to 22 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 how this vaccine works, with a view to inform general understanding on the mechanisms of protection against tuberculosis.

The study has demonstrated protection approximately during two years of study follow up. The final analysis of the study is expected to provide data on protection during 3 years of follow-up. Further investigation is needed to provide information about protection beyond 3 years in different populations.

WHO has recently expressed a preference for a level of protection against tuberculosis in adults exceeding 50% efficacy to deliver impact. 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 existing tuberculosis vaccine, BCG, is recommended for vaccination at birth to reduce the risk of severe forms of tuberculosis in children. While BCG provides moderate protection against severe forms of TB in infants and young children, it does not adequately protect adolescents and adults, who account for the majority of TB transmission. In this regard, these are very important findings in tuberculosis vaccine research. WHO with independent experts and formally constituted advisory committees will review the data and further assess the lessons for the field.

The study is still ongoing and a final analysis of the clinical data by the study sponsors is expected in 2019. Once the final results are analyzed, WHO encourages the planning of a well-designed Phase III program. Various priorities can be highlighted, with a view to generate 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 latent 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 in 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.