The Bill & Melinda Gates Foundation and the Wellcome Trust announced on Wednesday that they would jointly fund a $550-million Phase 3 clinical trial of M72, a new candidate vaccine against pulmonary tuberculosis, in several countries, including South Africa.

If it works, it will be the first new TB vaccine in more than 100 years and the first that is efficacious in teenagers and adults. The Phase 3 trial will run until earliest 2027 but could go on as long as 2029.

Current situation

The only TB vaccine currently available is Bacille Calmette-Guérin (BCG), which was first used in 1921.

It is given to babies and young children to protect them from TB, but offers only limited protection against pulmonary TB for adolescents and adults.

Dr Trevor Mundel, the head of Global Health at the Bill & Melinda Gates Foundation, said this week that M72 had shown much promise in preventing TB in people with latent infections, but who are not ill. This, he pointed out, was an important segment of the population to target.

He explained that, unlike Covid-19, for example, animal studies do not provide very accurate results for TB vaccines.

Burden of disease

The World Global TB Report, released in November 2022, shows the devastating impact of the disease on South Africa. It is estimated that 304,000 people in the country fell ill with TB in 2021 and 56,000 died. Tuberculosis remains one of the leading causes of death in SA.

Globally, TB claimed 1.6 million lives in 2021 and an estimated 10.6 million 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.

What will happen if it is proven to be effective?

“If proven effective, M72 could potentially become the first new vaccine to help prevent pulmonary tuberculosis in more than 100 years,” a joint statement by Wellcome and the Bill & Melinda Gates Foundation reads.

In the Phase 2b trial, M72 showed approximately 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 clinical trial?

The Phase 3 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 the Phase 3 trial will enrol about 26,000 people, including people living with HIV and without TB infection at more than 50 trial sites in Africa and Southeast Asia.

Mundel said that before the Phase 3 trial, a large epidemiological study was done to identify appropriate sites.

Nomathamsanqa Majozi, the head of Public Engagement at the Africa Health Research Institute in KwaZulu-Natal, said where she lives and works, “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.

“I would like to talk about the catastrophic cost of TB,” she said during the press briefing announcing the funding of the trial. “TB affects people in their prime working years. Families are left without an income. They suffer a huge economic setback. Their income goes toward TB treatment and associated costs (like transport).

“If you are from a low-income household, getting TB is catastrophic. Many people have to choose between TB treatment and getting basic necessities for the family.

“An effective vaccine will improve the outcomes for so many.  M72 offers us new hope for a TB-free future.”

To support the M72 Phase 3 clinical trial, Wellcome is providing up to $150-million, and the Gates Foundation will put in about $400-million.

Julia Gillard, the chair of Wellcome, said: “TB remains one of the world’s deadliest infectious diseases. The development of an affordable, accessible vaccine for adults and adolescents would be game-changing in turning the tide against TB. Philanthropy can be a catalyst to drive progress, as shown by this funding of the M72 vaccine as a potential new tool in preventing escalating infectious diseases to protect those most affected. 

“Sustainable progress against TB and wider disease threats will depend on global collaboration, financial backing and political will. By working with communities and researchers in countries with a high burden of the disease, we can take one step closer to eliminating TB as a public health threat.”

Bill Gates, the co-chair of the Bill & Melinda Gates Foundation, said, “With TB cases and deaths on the rise, the need for new tools has never been more urgent. Greater investment in safe and effective TB vaccines alongside a suite of new diagnostics and treatments could transform TB care for millions of people, saving lives and lowering the burden of this devastating and costly disease.”

The World Health Organization has estimated that a vaccine with at least 50% efficacy can, in the next 25 years, prevent 76 million new TB cases, 8.5 million deaths, 42 million courses of antibiotic treatment, and save $41.5-billion 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 good for HIV+ people.

“I am super excited about this,” he said.

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 stressing that the vaccine, if efficacious, will be vital in the fight against the disease.

Alex Pym, the director of Infectious Disease at Wellcome, said TB is 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 and this made the process of developing a TB vaccine much longer.

“The challenge is big. We need new approaches and tools,” he said. “A TB vaccine will really be a game-changer. There is a need for TB innovation.”

Mundel said the trial would probably last for four to six years. DM