The first jabs in a much-anticipated clinical trial of an experimental tuberculosis (TB) vaccine have been administered at a clinical trial site at the University of the Witwatersrand, writes Marcus Low for Spotlight, with up to 20 000 people expected to take part in the study.
Sponsored by the Bill and Melinda Gates Medical Research Institute (Gates MRI), it will be conducted at 60 sites in South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia and Vietnam.
Between 50% and 60% of the study participants will be in South Africa.
The experimental shot, called M72/AS01E (M72 for short), made waves in 2018 and 2019 when it was found to be around 50% effective at preventing people with latent TB infection from falling ill with TB over a three-year period in a phase 2b clinical trial.
In June last year, it was announced that after some delays, $550m in funding had been secured for a phase 3 study. Medicines or vaccines are typically only registered and brought to market after being shown to be safe and effective in large, phase 3 clinical trials.
While most cases of TB can be cured using a combination of four antibiotics for four or six months, TB rates are declining relatively slowly and it is widely thought that an effective vaccine would help bring infection rates down more quickly.
The WHO estimates that at the level of protection seen in the phase 2b trial, the vaccine could potentially save 8.5m lives and prevent 76m people from getting TB over a 25-year period.
The one TB vaccine we already have – Bacille Calmette-Guerin (BCG) – is more than a century old and provides only limited protection against severe illness for children, and no protection for adolescents or adults.
“Reaching phase 3 with an urgently needed TB vaccine candidate is an important moment for South Africans because it demonstrates a strong local and global commitment to fighting a disease that remains distressingly common in our communities,” said Dr Lee Fairlie, national principal investigator for the trial in South Africa.
Fairlie is also director of Maternal and Child Health at the Wits Reproductive Health and HIV Institute.
The initial response from TB activists was positive.
“TB Proof (a South African TB advocacy group) is delighted that the M72 phase 3 trial has been launched,” the organisation’s Ruvandhi Nathavitharana and Ingrid Schoeman told Spotlight. “Having an effective vaccine is critical for TB elimination efforts.”
How the study will work
Half of the up to 20 000 study participants will receive the M72 jab and the other half a placebo. The vaccine is administered as two intramuscular injections given a month apart. After being jabbed, study participants, aged 15 to 44, will be followed for four years from the date of the first study participant being enrolled.
“The plan is to complete enrolment in two years,” said Fairlie and Alemnew Dagnew, clinical lead for the trial.
The actual duration of the trial would depend on how long it takes for 110 people in the study to fall ill with TB. The study is expected to take around five years to complete.
Fairlie and Dagnew said most participants (around 18 000 people) will be HIV negative with latent TB infection, i.e, people with TB bacteria in their lungs, but who are not sick with TB.
Latent TB infection is thought to be very common in South Africa, and only around 10% of people with latent infection ever fall ill with the disease.
In the study, latent infection will be tested for using a type of test called an IGRA (Interferon-Gamma Release Assay).
Around 1 000 HIV negative people with no TB infection will also be recruited to the study, to ensure the vaccine is safe and effective in this group. While latent infection will be tested for, in the real world, such testing may not always be feasible before vaccination.
It is anticipated that 1 000 of the 20 000 study participants will be people with HIV. Establishing how well the vaccine works in this group is important since around 13% of South Africans are HIV+, which substantially increases the risk of falling ill with TB.
The main phase 2b study of M72 did not include people with HIV, although another phase 2 study looked specifically at the safety and immunogenicity of M72 in these people. According to Fairlie and Dagnew, that trial was completed and supported the inclusion of such participants in a phase 3 trial.
Smaller than planned
When funding for the phase 3 trial was announced last year, it was estimated that 26 000 people would participate, but that has been revised down to 20 000.
“After ongoing discussions, the decision was taken to review the study protocol with the intent of simplifying it, given its size and complexity. This will not affect the safety … It is common to continue to refine a protocol. We found a way to expedite the study that would potentially allow us to offer the public health impact of this vaccine to those in need sooner,” said Fairlie and Dagnew.
Planning for access
The development of M72 has taken a somewhat unusual path, with GSK leading development until the end of phase 2b and then largely passing the baton to Gates MRI with the conclusion of a licensing deal in 2020.
GSK has been criticised for heel-dragging after the initial publication of the phase 2b results in 2018, with some suggesting this was because GSK were focusing on more profitable vaccines.
However, it continues to provide technical assistance to the Gates MRI, supplying the adjuvant component of the vaccine for the phase 3 trial, and will provide the adjuvant post licensure if the trial is successful.
But the ongoing dependence on a single company for the adjuvant worries some activists. “We are concerned about reports that scaling this vaccine may be difficult because of limited availability of the adjuvant. Access for everyone who needs it should be part of the early phases of the research process – not an afterthought,” said Nathavitharana and Schoeman.
“Part of the unspoken complexity is the opaque licensing deal GSK and Gates MRI signed in 2020 where GSK gave rights to develop and commercialise M72 to Gates MRI while retaining control over the AS01E adjuvant,” said Frick.
“This could work against equitable access, but terms of the licence remain unknown to the public.”
Gates MRI said its collaboration with GSK “includes provisions to ensure sufficient supply of adjuvant for the clinical development and first adoption in low-income countries, at an affordable price, if it is approved for use”.
See more from MedicalBrief archives:
SA in five-country trials for drug-resistant TB treatment
SA in multi-million-dollar trial for new TB vaccine
New TB drug shows promise in phase 2 trials