Interview with Dr. Alemnew Dagnew, Clinical Leader for M72 TB Vaccine at Gates MRI » Capital News
1. Could you provide an overview of the M72/AS01E TB vaccine candidate and its development history? What makes the M72/AS01E vaccine candidate promising compared to other TB vaccines in development?
The M72/AS01E vaccine candidate was developed by GSK in partnership with Aeras and IAVI. The candidate comprises an immunogenic fusion protein (M72) and the AS01E adjuvant system. It is derived from two Mycobacterium tuberculosis antigens (MTB32A and MTB39A). These antigens were selected based on strong immune (T-cell) responses to these antigens in healthy people with a positive TB skin test (PPD-positive). The vaccine candidate demonstrated the ability to generate an effective and durable immune response specific to the two vaccine candidate’s antigens in humans.
2. Can you explain the objectives of the Phase 3 clinical trial for the M72/AS01E TB vaccine candidate in Kenya?
Kenya is one of 7 countries that will take part in this clinical trial. At full capacity, the trial will include up to 20,000 participants, including people living with HIV, at up to 60 trial sites in South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia and Vietnam. Participants will receive either the investigational M72/AS01E vaccine or a placebo in what is known as a double-blind trial, meaning neither the trial participant nor the clinical investigators will know who receives vaccine or placebo. This approach is considered the gold standard for evaluating the safety and efficacy of an investigational vaccine.
3. What have been the key findings from earlier stages of testing for this vaccine?
The M72/AS01E vaccine candidate has been in development since the early 2000s. It was originally designed and clinically evaluated by the biopharma company GSK up to the proof-of-concept phase (Phase 2b), in partnership with Aeras and the International AIDS Vaccine Initiative (IAVI) and was funded by GSK and in part by the Gates Foundation. In 2020, GSK announced a partnership with the Gates MRI for further development of M72/AS01E. GSK continues to provide technical assistance to the Gates MRI, supplies the adjuvant component of the vaccine for the Phase 3 trial and will provide the adjuvant post licensure should the trial be successful. An adjuvant is an ingredient used in some vaccines that can help create a stronger immune response.
In GSK’s Phase 2b trial, M72/AS01E provided approximately 50% protection against progression to active pulmonary tuberculosis for three years in Mycobacterium tuberculosis-infected HIV-negative adults, which was unprecedented in decades of TB vaccine research. The World Health Organization estimates that over a 25-year time span, that level of protection could save 8.5 million lives, prevent 76 million new TB cases and save $41.5 billion for TB affected households.
4. Why were Kisumu, Kilifi, Machakos, and Nairobi chosen as the initial trial sites in Kenya?
Nine trial sites have been selected in Kenya, and they are at different phases of obtaining the required approvals from ethics committees and health authorities to start the trial. The sites in Kisumu, Kilifi, Machakos, and Nairobi have already obtained the necessary approvals, and the others will follow as they secure their required approvals
5. How is the Bill & Melinda Gates Medical Research Institute (Gates MRI) contributing to this trial, and what other organizations are involved?
The Gates MRI, a nonprofit medical research organization, is sponsoring the trial, which is supported by funding from the Gates Foundation and Wellcome.
The “sponsor” in regulatory terms is the legal entity with overall accountability for a clinical trial. The sponsor is responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the protocol and regulatory expectations (good clinical practice, scientific & medical oversight, data integrity, safety oversight and reporting, etc.). GSK was the sponsor of the Phase 2b study as the original developer of the vaccine. Under the license from GSK, Gates MRI is leading onward development and is therefore the sponsor of Phase 3.
6. What are the expected outcomes of the Phase 3 clinical trial in terms of vaccine efficacy and safety?
The trial will evaluate the vaccine efficacy (VE) of M72 in the prevention of laboratory-confirmed pulmonary TB among IGRA-positive participants. If shown to be well-tolerated and effective with acceptable safety profile, M72 could potentially become the first vaccine to help prevent pulmonary TB in adolescents and adults, the most common form of the disease, and the first new TB vaccine in over a century.
7. How will the findings from this trial impact the fight against TB in Kenya and globally, particularly for adolescents and adults?
A novel TB vaccine is critical to the vision of a world without TB. Developing an effective TB vaccine with an acceptable safety profile for adolescents and adults could offer a powerful way of helping to curb new cases and stop people from progressing to active TB disease, thereby helping to stop the spread of TB. Adolescents and adults bear the highest burden of pulmonary TB and therefore are responsible for the majority of transmission. By helping to prevent TB in these age groups, a vaccine could help protect people of all ages. The World Health Organization estimates that over a 25-year time span, a vaccine with 50% efficacy for protecting adolescents and adults could save 8.5 million lives, prevent 76 million new TB cases and save $41.5 billion for TB affected households.
8. What are the next steps if the Phase 3 trial results are positive?
We anticipate the trial will take approximately 5 years to complete, followed by a detailed statistical analysis of results prior to submission for regulatory approvals. We will be able to refine our guidance on timings as the trial progresses.
9. How could this vaccine change the landscape of TB prevention globally, especially in high-burden countries like Kenya?
A novel TB vaccine is critical to the vision of a world without TB. Developing an effective TB vaccine with an acceptable safety profile for adolescents and adults could offer a powerful way of helping to curb new cases and stop people from progressing to active TB disease, thereby helping to stop the spread of TB. Adolescents and adults bear the highest burden of pulmonary TB and therefore are responsible for the majority of transmission. By helping to prevent TB in these age groups, a vaccine could help protect people of all ages. The World Health Organization estimates that over a 25-year time span, a vaccine with 50% efficacy for protecting adolescents and adults could save 8.5 million lives, prevent 76 million new TB cases and save $41.5 billion for TB affected households.
If a new TB vaccine were used widely, it could have the potential to help reduce drug-resistant TB by reducing transmission and preventing the need for antibiotics use – a critical step for curbing antimicrobial resistance. TB is one of the leading drivers of antimicrobial resistance and decreasing TB could substantially decrease inappropriate antibiotic use because people with common symptoms of TB including cough and fever, for example, are often prescribed inappropriate antibiotics before they are put on appropriate TB treatment.
10. Assuming the vaccine proves effective, what are the plans for manufacturing and distributing it within Kenya and other affected regions?
Making vaccines accessible and affordable for communities in areas of high disease burden in the long-term is a priority for all trial partners. The Gates MRI has worked with a wide range of stakeholders, including communities around clinical trial sites, to guide the TB candidate vaccine to Phase 3. To this end, the Gates MRI, GSK, Wellcome and the Gates Foundation are working together to understand the potential demand for the vaccine and build an end-to-end plan to ensure long-term sustainable access, should the trial be successful; from supporting research and building an evidence-base for the potential impact of the vaccine and community requirements for uptake, to collaborating with multilateral, regional and country partners required to introduce the vaccine.
Additionally, the trial funders are planning to establish an international advisory group comprised of representatives from all these groups to provide input on the overall program.
Developing and ensuring access to global health products is a complex task. As such, global collaboration and strong partnerships are a core component of planning for future access to the candidate vaccine.
11. How will the vaccine be priced, and what measures are being considered to ensure it is accessible to those who need it most, especially in low-income communities?
We are not able to answer questions about the price of M72 at this time with the rollout of the vaccine candidate, if successful in Phase 3 trials, not anticipated for several years. We will be working on such topics in the coming months.
12. What steps are being taken to engage with local communities and stakeholders to foster trust and support for the trial?
Community involvement is a key element in each stage of clinical development. The team at the Gates MRI worked with a global TB Community Advisory Board (CAB) and a local CAB in South Africa to discuss the overall program and the design of the phase 3 trial. In addition, there are 2 CAB members on the Trial Steering Committee, one from Asia and one from Africa. Sites are working with their own local CABs.
13. What systems are in place for monitoring the safety and efficacy of the vaccine during the trial?
As the sponsor of the clinical trial, the Gates MRI is responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the protocol and regulatory expectations (good clinical procedures, scientific & medical oversight, data integrity, safety oversight and reporting, etc.)
14. How does the M72/AS01E vaccine candidate compare with other TB vaccines currently available or in development?
M72/AS01Eis the most clinically advanced subunit vaccine in development for TB. It has different antigens and a different adjuvant[1] compared to other candidates. It is the first vaccine candidate to be evaluated in an adult population with latent TB infection, and it is the first subunit vaccine candidate ever to demonstrate efficacy against pulmonary TB in adults, the most common manifestation of the disease in people. It has met key criteria for the WHO’s preferred product characteristics for new adult/adolescent TB vaccines.
15. What role does this vaccine play in the broader strategy for TB prevention and treatment, particularly in comparison to existing treatments and preventive measures?
A novel TB vaccine is critical to the vision of a world without TB. Developing an effective TB vaccine with an acceptable safety profile for adolescents and adults could offer a powerful way of helping to curb new cases and stop people from progressing to active TB disease, thereby helping to stop the spread of TB.
Adolescents and adults bear the highest burden of pulmonary TB and therefore are responsible for the majority of transmission. By helping to prevent TB in these age groups, a vaccine could help protect people of all ages. The World Health Organization estimates that over a 25-year time span, a vaccine with 50% efficacy for protecting adolescents and adults could save 8.5 million lives, prevent 76 million new TB cases and save $41.5 billion for TB affected households.
16. What is the long-term vision for TB eradication in Kenya and globally, and how does the M72/AS01E vaccine fit into this vision? Already addressed in Q7. Many countries have been making significant and sustained progress in controlling TB. But the rate of decline is slower than what is needed to meet targets set by the global health community and by many countries themselves. An effective vaccine for all adolescents and adults could speed up those efforts. To accelerate progress, novel TB vaccines, diagnostics, and treatments must be used alongside efforts to address over-crowding, poor nutrition, HIV, diabetes, and other risk factors for TB.
17. How important is international collaboration in the fight against TB, and what role do global partnerships play in the success of the M72/AS01E vaccine trial?
International collaboration is a vital element in the fight against TB and the partnership between the Gates MRI, GSK, the Gates Foundation and Wellcome have been pivotal in driving the progress of the M72 program.
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