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Ambitious clinical trial could bring first TB vaccine in a century

June 4, 2024

A cluster of overlapping orange rod shapes on a purple background.Photo courtesy of NIAIDScanning electron micrograph of Mycobacterium tuberculosis particles (colorized orange), the bacterium which causes TB.

Phthisis, wasting disease, consumption, the white death—tuberculosis (TB) has been known by many names in the past and even appears in the writings of Hippocrates (460-355 BC). Though ancient in origin, this infectious disease remains a scourge in our own time, having killed 1.3 million people in 2022, with an additional 10.6 million falling ill that same year. Notably, this respiratory disease, which is triggered by a form of bacteria (Mycobacterium tuberculosis), is the leading cause of death among people living with HIV/AIDS. Overall, nearly a quarter of the world’s population has a latent TB infection; free of symptoms, these people are unable to spread TB to others, yet some will progress to active illness. Today's TB patients are often young adults residing in low- and middle-income countries. Though most sufferers can be cured with antibiotics, multidrug-resistant TB is increasingly prevalent and threatens to become a crisis.

Meanwhile, the only licensed vaccine for TB was developed more than 100 years ago by Albert Calmette and Jean-Marie Camille Guerin. A milestone achievement in 1921, the Bacille Calmette-Guerin (BCG) vaccine remains in widespread use today to prevent TB in infants and young children. It shows variable efficacy against different forms of TB, however, with most consistent protection observed against certain forms of the disease that occur outside the lungs. As this vaccine's protection diminishes over time, teens and adults are left vulnerable to pulmonary tuberculosis, which accounts for most infections and deaths in these age groups.

A possible breakthrough is in progress. In March 2024, scientists in seven countries launched a Phase 3 trial of an investigational TB vaccine, the M72/AS01E. In a previous Phase 2B trial, this innovative inoculation had stopped progression from latent to active TB in half of the adults who participated in the study. 

“Fogarty has been proud to support decades of research and research training around the world to address the scourge of tuberculosis, including multidrug-resistant TB," said Dr. Peter Kilmarx, Fogarty's deputy director. "We’re excited to see the global roll-out of the M72/AS01E vaccine trial and hope this will be a powerful new tool for the prevention of active TB disease and deaths worldwide.”

Accelerating vaccine development

During the COVID-19 pandemic, global annual spending on essential TB services fell from $6 billion in 2019 to $5.4 billion in 2021. While this may not seem like a dramatic drop, it falls below funding targets set by the WHO's End TB Strategy, which aims to reduce global TB incidence by 80% by 2030. To stimulate investment, WHO Director-General Dr. Tedros Ghebreyesus announced at the World Economic Forum in January 2023 the establishment of a WHO TB Vaccine Accelerator to identify and overcome barriers to TB vaccine development, licensing and use. M72/AS01E is one of 17 TB vaccine candidates in clinical development as part of this program.

The M72/AS01E vaccine was originally designed by biopharmaceutical company GSK and the International AIDS Vaccine Initiative, a nonprofit research organization. It contains a M72 recombinant fusion protein, derived from two TB antigens (Mtb32A and Mtb39A); fusion proteins are synthesized to contain unique structural features, different from their “parent” proteins, that are recombined to effectively function ;within a synthetic pharmaceutical formulation. Pharmacologists combined the M72 protein with a GSK-trademarked adjuvant (immunogenicity enhancer), known as AS01E, to help amplify the body’s immune response to the resulting vaccine.

Following the successful Phase 2b trial of M72/AS01E in 2019, the nonprofit Bill & Melinda Gates Medical Research Institute (Gates MRI) licensed the vaccine, intending to push it through to completion of clinical studies. This is all part of the Gates MRI's overall market strategy. “We build the middle piece of the development process—we license the entity and drive it all the way to registration,” Emilio Emini, the non-profit’s former chief executive officer recently told The Lancet. If successful, Gates MRI will then sub-license the M72/AS01E vaccine to a manufacturer capable of making it available at "a price that those in need can afford."

Scientists and patients eagerly await the results of this Phase 3 trial. The double-blind study, led by Dr. Alemnew Dagnew for Gates MRI, aims to enroll up to 20,000 participants at 60 trial sites across South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia, and Vietnam. Participants, who include people living with HIV, will receive either M72/AS01E or a placebo. The investigators expect the trial, funded in part by Wellcome Trust, to take at least five years to complete.

More Information

Updated June 11, 2024

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