South Africa is among the countries which will take part in a $550m phase three clinical trial of M72, a new candidate vaccine against pulmonary TB,which, if successful, will be the first new in more than 100 years and the first that is efficacious in teenagers and adults.
The 26 000-person trial is jointly fudnded by the Bill & Melinda Gates Foundation and the Wellcome Trust and will begin next year and run until earliest 2027 but could go on as long as 2029.
The M72/AS01 vaccine showed promising results from a smaller trial in 2019, the findings stoking excitement at the time.
But a larger, confirmatory study was delayed as GSK, the company then developing it, transferred the shot to the Gates Medical Research Institute, an affiliate of the foundation, rather than move forward with the vaccine itself, reports STAT News.
“We experienced quite a bit of frustration with how long it took,” said Thomas Scriba, a University of Cape Town immunologist and an investigator on both studies, calling the news “an unbelievably positive development … the world really needs a TB vaccine.”
Current situation
The only TB vaccine currently available is Bacille Calmette-Guérin (BCG), which was created by a French team and first used in 1921.
Made from the bacteria that causes bovine tuberculosis, it is given to children in many middle- and low-income countries, but studies measuring its effectiveness have shown mixed results, and it doesn’t protect adolescents or adults.
Dr Trevor Mundel, head of Global Health at the Bill & Melinda Gates Foundation, said M72 had shown much promise in preventing TB in people with latent infections, but who are not ill, reports Daily Maverick.
This, he pointed out, was an important segment of the population to target.
Burden of disease
The World Global TB Report, released in November 2022, shows the devastating impact of the disease on South Africa where it is estimated that 304 000 people fell ill with TB in 2021 and 56 000 died. It remains one of the leading causes of death in the country.
Globally, TB claimed 1.6m lives in 2021 and an estimated 10.6m people fell ill with it. The disease primarily affects low- and middle-income countries.
It is further estimated that as much as 24% of the world’s population has latent TB, meaning they are infected, but not ill. They are at greater risk, though, of developing TB.
How does M72 work?
The M72 vaccine candidate contains the M72 recombinant fusion protein, derived from two antigens (Mtb32A and Mtb39A) of the Mycobacterium tuberculosis, the bacteria that causes TB. The antigens are combined with the GSK adjuvant system.
An antigen is a toxin that produces an immune system response in the body. An adjuvant is used in some vaccines to boost that immune response.
There are four other candidate vaccines for TB in the Phase 3 clinical trial stage, but M72 is the only one that works in this way.
In the phase 2b trial, M72 showed 50% efficacy in reducing pulmonary TB in adults with latent TB infection, unprecedented in decades of TB vaccine research.
What will be investigated by the trial?
The phase three clinical trial will assess M72’s efficacy in preventing the progression from latent TB infection to pulmonary TB, a form of active TB.
It will be conducted in collaboration with an international consortium of TB clinical investigators, and will enrol about 26 000 people, including people with HIV and without TB infection at more than 50 trial sites in Africa and Southeast Asia.
Mundel said that before the trial, a large epidemiological study was done to identify appropriate sites.
Nomathamsanqa Majozi, head of public engagement at the Africa Health Research Institute in KwaZulu-Natal, said: “more than half of all people have had, or will have, TB at some point in their lives”.
She said more than 500 people were diagnosed daily with TB in South Africa.
“An effective vaccine will improve the outcomes for so many. M72 offers us new hope for a TB-free future.”
The WHO has estimated that a vaccine with at least 50% efficacy can, in the next 25 years, prevent 76m new TB cases, 8.5m deaths, 42m courses of antibiotic treatment, and save $41.5bn in health, economic and societal costs, especially for the world’s poorest and most vulnerable people.
Affordability
Mundel said making the vaccine as affordable and as accessible as possible would be very important. Apart from South Africa, clinical trials will be conducted in Vietnam, the Philippines, Malaysia and Peru, where there are high levels of the disease.
“But the highest levels of TB are still in South Africa,” he said, adding that the safety of the vaccine looks encouraging for HIV+ people.
Their preliminary work showed that the vaccine was providing durable protection.
“TB is an unusual bug. It has co-evolved with humans for thousands of years,” he said adding that the vaccine, if efficacious, would be vital in the fight against the disease.
Alex Pym, the director of Infectious Disease at Wellcome, said TB was one of the biggest health challenges in the world. “Treatment is still four to six months long. Diagnostics can still not diagnose early enough to prevent transmission,” he said.
Added to that is the threat of latent TB. He said the human immune response to TB was much more complex than to an acute viral infection, which made the process of developing a TB vaccine much longer.
“The challenge is big. We need new approaches and tools,” he said. “A vaccine will really be a game-changer. There is a need for innovation.”
“It’s really a big deal,” Maziar Divangahi, associate director of the McGill International TB Centre told STAT. “If this vaccine could reduce the disease by 50%, that has tremendous implications worldwide.”
Such a reduction, he said, could significantly curb TB transmission, as people with latent infection can’t spread the bacteria.
Divangahi cautioned, however, against putting too much faith in the 2019 results. In that trial, 39 people – 26 in the placebo group, and 13 in the vaccine group – became sick, so the sample size was “extremely low”, he said. And no one knows how long protection might last.
Although the Gates Medical Research Institute is assuring in manufacturing the vaccine, GSK will continue supplying an adjuvant, a molecule designed to amplify the vaccines’ signal to the immune system.
A GSK spokesperson said that given the complexity of running a phase three trial in lower-income countries, the company believed the institute was the best organisation to move forward with the vaccine, and that GSK’s “most important contribution to global health is the science, investigating proof-of-concept through phase two”.
If the vaccine succeeds, the Gates Foundation’s work will be far from over. Mundel said the foundation would need to find a partner to manufacture the drug for a commercial market.
And given that TB primarily affects the poorest groups in low-income countries, experts warn roll-out will be daunting.
Although latent TB can already be treated with antibiotics, those drugs require people to take pills for at least a month.
Many low-income countries don’t have the extensive resources required to identify and dose infected individuals.
A two-dose shot should be more scalable, said Mel Spigelman, CEO of TB Alliance, but it “will still be a very expensive and daunting task” to find and dose potentially billions of people.
“That will require a lot of resources,” he said, “that aren’t presently being devoted to TB.”
See more from MedicalBrief archives:
TB remains the world’s deadliest infectious disease — WHO report
Encouraging results from study into new TB vaccine
Candidate vaccine significantly reduces pulmonary TB in trial
Treatment gaps and poor governance hold back progress in reducing TB