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Promising Tuberculosis Vaccine Gets US$550-million Shot In The Arm

A 3D computed tomography chest scan of a patient with tuberculosis.Credit: Vsevolod Zviryk/Science Photo Library

A promising vaccine candidate for tuberculosis is getting a new lease of life after two major funders have decided to pour US$550 million into its final phase of clinical trials. If successful, it would be the first new tuberculosis vaccine on the market in more than a century.

"TB has been chronically underresourced, underfunded and underappreciated for a very long time," says Thomas Scriba, the deputy director of the South African Tuberculosis Vaccine Initiative, who will be involved in the trials.

The Bill & Melinda Gates Foundation and Wellcome announced the funding on 28 June. The vaccine candidate was developed by drug firm GSK, which has licensed it to the Gates Medical Research Institute.

Tuberculosis, caused by Mycobacterium tuberculosis, is one of the world's biggest epidemics, claiming 1.6 million lives each year. The burden is particularly high in low- and middle-income countries. This disparity was dramatically showcased during the COVID-19 pandemic, when disruptions to health services led to increased infections.

A major challenge in fighting tuberculosis is that the bacterium can hide in the body for years before becoming an active infection that shows symptoms. Estimates suggest that one in four people globally carry this latent infection. And although the BCG vaccine (short for Bacillus Calmette-Guerin) — which was developed in 1921 and remains the only available jab against tuberculosis — protects children effectively, it offers limited help in adults.

The vaccine candidate, called M72/AS01E, aims to tackle the latent infections. And it showed promise in data published from phase II trials in 2019, demonstrating a 54% efficacy in adults who hosted the bacterium. But GSK abandoned it owing to a lack of commercial potential.

Moving to phase III trials is long overdue, says Scriba. "It's entirely appropriate that there's substantial investment in this field so that we can actually appropriately respond to the magnitude of the TB problem," he adds. The trial will recruit 26,000 participants in several countries across Asia and Africa.

M72/AS01E consists of a fused protein called M72 — comprised of two M. Tuberculosis antigens — and an adjuvant, AS01E. Researchers chose the antigens on the basis of their high immunogenicity — a strong ability to provoke the immune system, which stimulates the crucial T-cell response needed to fight the bacteria and to create memory cells for future attacks.

Although active tuberculosis is treatable with a six-to-nine-month course of antibodies, the lengthy process has led to high incompletion rates and antibiotic resistance. The lack of access to treatment for those in poverty also remains a barrier.

The investment in the vaccine candidate is an acknowledgement of the gap that needs to be addressed in preventing tuberculosis, says Alexander Pym, Wellcome's director of Infectious Disease. A new vaccine would be a gamechanger, he adds.

And a handful of other tuberculosis vaccine candidates in phase III trials offer hope that a new method of prevention will reach people soon. But M72/AS01E so far surpasses the rest in the quantity and quality of data, says Ajit Lalvani, the director of the Tuberculosis Research Unit at Imperial College London.

"I'm confident that by the end of this decade, we will have a new TB vaccine on the shelves, and hopefully more than one," says Scriba.

South Africa: Funding Secured For Massive TB Vaccine Trial

A massive and much-anticipated phase 3 trial of an experimental tuberculosis (TB) vaccine is set to proceed after funding for it has been secured from two large philanthropies. Wellcome and the Bill & Melinda Gates Foundation (BMGF) Wednesday announced they'd be investing a combined $550 million into the trial – around $150 million from Wellcome and the remaining from the Bill & Melinda Gates Medical Research Institute, a nonprofit subsidiary of the BMGF.

The vaccine, called M72/AS01E or just M72, made headlines in September 2018 when it was found to offer 54% protection against pulmonary TB disease in a phase 2B trial. That trial, of around 3 300 people, was conducted in South Africa, Zambia, and Kenya. Final results from that study were published in the New England Journal of Medicine in 2019 –- efficacy in these final results was down to around 50%.

Medicines and vaccines are typically only brought to market once safety and efficacy have been confirmed in a large phase 3 trial. In this case, the phase 3 trial is set to have around eight times as many participants as the phase 2B trial.

26 000 study participants

"Conducted in collaboration with an international consortium of TB clinical investigators, the trial will enroll approximately 26 000 people, including people living with HIV and without TB infection, at more than 50 trial sites in Africa and Southeast Asia," Wellcome and BMGF said in a statement announcing the trial.

They said the trial will "assess the candidate vaccine's efficacy at preventing progression from latent TB infection to pulmonary TB". In an online media conference on Wednesday Trevor Mundel, President for Global Health at BMGF, clarified that while most study participants will be people with latent TB infection, 4 000 people without TB infection would also be recruited. This is because establishing evidence of the vaccine's safety in people without latent TB infection will be important if the vaccine is to be rolled out in areas with high background rates of TB without first having to test everyone for latent infection. "You'd want to be comfortable with vaccinating everyone in the community," he said, "So we need to have that safety data in the uninfected as well in order to be able to have that usage, which will be the easiest way to use the vaccine at the end of the day."

Mundel said that the study is scheduled to start early in 2024 and that it is expected to last for four to six years. Exactly how long the study will take will depend largely on how long it takes for 150 study participants to develop active TB – the number required for the study to have sufficient statistical power. By comparison, recruitment for the phase 2B trial started in 2014 and the first findings from that study were published in 2018.

According to the statement, additional details about the trial design and participants will be announced in the coming months.

Given that the phase 2B trial was partially conducted in South Africa and the country has substantial TB clinical trial capacity, it is almost certain that some of the 50 trial sites will be in South Africa – although know specific trial sites have yet been announced.

As pointed out in the statement, the only TB vaccine in use today, bacille Calmette-Guerin (BCG), was first given to people in 1921. It helps protect babies and young children against severe systemic forms of TB but offers limited protection against pulmonary TB among adolescents and adults. If the findings from the phase 3 trial of M72 are positive, m72 will become the first new TB vaccine in over a hundred years to be proven safe and effective.

According to the most recent figures from the World Health Organization (WHO), around 304 000 people fell ill with TB in South Africa in 2021. While TB rates are declining, they are declining relatively slowly and according to the most recent WHO World TB Report, a major technological breakthrough such as a new vaccine will be needed if ambitious TB control targets are to be met.

Announcement welcomed

"We've waited a long time for this study, so are happy to see the Bill & Melinda Gates Foundation and Wellcome taking up this important task," said Patrick Agbassi, chair of the Global TB Community Advisory Board, in a comment included in the Wellcome/BMGF statement. "The question now becomes how we can enroll 26 000 people most quickly and ensure that all populations at risk of TB will ultimately be able to benefit from access to what could be the first new TB vaccine in over 100 years. A robust community engagement programme will be key, as will taking on studying this vaccine in younger adolescents, pregnant women, people with prior history of TB, and other key groups often underrepresented or left out entirely of TB trials and the benefits of scientific progress."

Mark Harrington, executive director of New York-based advocacy organisation Treatment Action Group (TAG) said, "TAG welcomes this historic investment in TB vaccine development by Wellcome and the Bill & Melinda Gates Foundation. A Phase III clinical trial of the M72/AS01E TB vaccine candidate is a long-awaited milestone. We hope this funding commitment sparks governments and other funders to substantially increase investments in the TB vaccine pipeline, which contains a number of promising candidates in addition to M72/AS01E but faces a dire financial shortfall."

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"This Phase III trial," Harrington said, "will take several years to complete. We encourage the Gates Foundation, Wellcome, GSK, country governments, and other partners to use this time to lay the groundwork for eventual vaccine adoption by ensuring the availability, affordability, and acceptability of M72/AS01E should it prove safe and effective."

Initial development of M72 was driven by the pharmaceutical company GSK with support from several governments, philanthropies, and research organisations. The vaccine contains the M72 recombinant fusion protein, which the Wellcome/BMGF statement explains is derived from two Mycobacterium tuberculosis antigens (Mtb32A and Mtb39A) combined with the GSK proprietary Adjuvant System AS01E. According to the statement, GSK will continue to provide the adjuvant for the vaccine's further development and potential launch.

National TB Indaba Reveals Way Forward for Retaking Control of Tuberculosis After Covid-19 Setbacks

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Gates Foundation And Wellcome To Fund Late-stage Trial Of Tuberculosis Vaccine Candidate

The Bill & Melinda Gates Foundation and Wellcome have joined forces to fund the late-stage development of what could be the first tuberculosis (TB) vaccine in over a century.

TB is a bacterial infection spread by inhaling tiny droplets from the coughs or sneezes of an infected person.

Despite being both curable and preventable, the disease continues to affect around ten million people every year, and 1.6 million people died from it in 2021, almost entirely in low and middle-income countries.

The only TB vaccine in use today, bacille Calmette-Guérin (BCG), was first used in 1921. It helps protect babies and young children against severe systemic forms of TB, but offers limited protection against pulmonary TB – a form of active TB – among adolescents and adults.

The Gates Foundation and Wellcome will invest around $550m to support the phase 3 trial of the M72/AS01E (M72) vaccine, which will be tested to see how well it prevents latent TB from becoming active TB and causing illness.

The study is expected to take four to six years and will enrol 26,000 people, including those living with HIV and without TB infection, at more than 50 sites across Africa and Southeast Asia.

M72 has already been shown in a phase 2b trial to prevent active TB from developing in around half of those who received it.

Julia Gillard, chair of the board of governors at 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.

The vaccine has been in development since the early 2000s by GSK in partnership with non-profit Aeras and the International AIDS Vaccine Initiative.

In 2020, the UK-based drugmaker announced that it would partner with the Gates Medical Research Institute for continued development and potential use of M72 in countries with a high TB burden, with GSK continuing to provide the adjuvant for the candidate's further development and potential launch.

Bill Gates, co-chair of the Gates Foundation, said: "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."

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