Q&A on the candidate vaccine for the M72 / AS01E trial

1. What is an M72 / AS01E vaccine candidate?

M72 / AS01E is a vaccine subunit consisting of an immunogenic fusion protein (M72) that originates from two Mycobacterium tuberculosis (M.tb) antigens (MTB32A and MTB39A) and the proprietary helper GlaxoSmithKline (GSK) AS01E. AS01E is the same adjuvant used in the Shingrix GSK vaccine as in the new RTS malaria vaccine, S / AS01E.

2. Who developed and who produced the vaccine?

The M72 / AS01E vaccine candidate is being developed by the pharmaceutical company GlaxoSmithKline, in partnership with AERAS. AERAS is a US-based nonprofit focused on supporting tuberculosis vaccine research and funded by the Bill and Melinda Gates Foundation, the British Ministry of International Development (DFID) and other organizations.

3. What is the role of the WHO in this trial?

WHO did not participate in the design or implementation of this test.

4. What is the Phase IIb Test on M72 / AS01E intended for?

The purpose of this ongoing study is to evaluate the safety, immunogenicity and protective efficacy of M72 / AS01E vaccine against pulmonary TB compared with placebo in HIV-negative adults with latent TB infection living in countries with many TB (South Africa, Kenya and Zambia) and ages 18 – 50. The study remains ongoing and a final analysis is planned in 2019.

• What is the trial design and current status

  This is a multicenter, double-blind, randomized, placebo-controlled trial that involved 3573 adult HIV-negative adults (18-50 years) in South Africa (2873 from South Africa, 162 from Zambia, 538 from Kenya) who had evidence of Mtb baseline infections (IGRA +) vaccinated with M72 / AS01E or placebo at 2 dose intervals administered at 1 month intervals. The primary endpoint was the development of pulmonary TB. This was a case-focused analysis, where the analysis was initiated by the accumulation of a number of cases of pulmonary TB. While the primary analysis is now published1, a study is ongoing, with final descriptive analysis planned for release in 2019.

• Can the vaccine cause unpleasant or dangerous reactions in people who are vaccinated?

  Individuals vaccinated with M72 / AS01E had more local and flu-like reactions than placebo recipients. There were no others regarding the security imbalance between the groups studied. The study remains blinded at the individual level. A complete reversal of the security data is expected during the final analysis.

• Performance results

  The results showed that administration of 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 participated in the primary vaccine efficacy analysis over two years of follow-up: 10 participants vaccinated with M72 / AS01E developed pulmonary TB compared with 22 participants in the placebo group.

5. How does the vaccine work?

The exact mechanism of action of M72 / AS01E is unknown. Previous studies have shown that this vaccine induces an immune response characterized by activation of CD4 + T-producing interferon-gamma and antibody production. WHO strongly encourages basic research to expand existing understanding of how this vaccine works, with a view to a general understanding of the mechanisms of tuberculosis protection.

6. Does this vaccine provide long-term or lifelong protection?

The study showed protection for approximately two years of follow-up. The final analysis of the study is expected to provide protection data over the 3 years of follow-up. Further investigation is needed to provide protection information after 3 years in different populations.

7. Is the reported efficacy sufficient to affect the burden and spread of the disease?

The WHO has recently expressed a preference for a degree of protection against tuberculosis in adults exceeding 50% of the efficacy to achieve the effect. It will be important to determine whether the current vaccine also protects people who are not infected with M.tb in different geographical regions.

8. Can the vaccine prevent the development of drug-resistant TB?

This was not evaluated in this study. However, the pulmonary tuberculosis vaccine in adults, if used extensively, can reduce drug-resistant tuberculosis by reducing transmission and preventing the need for antibiotics; essential steps to combat antimicrobial resistance. The role of this vaccine for the candidate in limiting the development and spread of drug resistant TB drugs should be further evaluated.

9. What is the provisional WHO position on results?

WHO welcomes the efforts made in partnership between GSK, AERAS, research researchers, study participants and countries to achieve this result.
The existing tuberculosis vaccine, BCG, is recommended for vaccination at birth to reduce the risk of more severe tuberculosis in children. Although BCG provides moderate protection against severe TB in infants and young children, it does not adequately protect adolescents and adults, who are a major part of TB transmission. In this regard, these are very important findings in the study of tuberculosis vaccines. The WHO, with its independent experts and formally formed Advisory Board, will review the data and further evaluate lessons for the area.

10. What should be the next steps?

The study is still ongoing and a final analysis of the clinical data by the study sponsor is expected in 2019. Once the final results are analyzed, WHO encourages the planning of a well-designed Phase III program. Different priorities can be highlighted to more accurately evaluate vaccine efficacy, in different geographical conditions, and further evaluate 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 people infected with HIV. This will require adequate production and financing of the vaccine. WHO calls on all relevant stakeholders, including pharmacists, funders, governments, civil society, healthcare practitioners, policy makers and international agencies, to act in a sense of urgency, in a spirit of collaboration and a sense of responsibility for public health, to make progress accelerating the validation of this products in the fight against tuberculosis.

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reference

Meeren O et al. Phase 2b controlled trial of M72 / AS01E vaccine for tuberculosis prevention. NEJM. 2018th