Tuberculosis
Tuberculosis
Introduction
Tuberculosis (TB) is an ancient disease that has affected humans for thousands of years. It remains the leading infectious cause of death worldwide. Each day, more than 3,400 people lose their lives to TB and close to 30,000 people fall ill with TB disease.
In 2024 alone, an estimated 10.7 million people developed active TB— including 1.2 million children— and 1.23 million people died from TB, including 150,000 people living with HIV. The disease burden remains greatest in lower- and middle- income countries (LMICs) with greater than 90% of the annual global TB burden occurring in LMICs and two-thirds of it occurring in 8 LMICs across Asia and Africa.
Though substantial progress has been made in the fight against TB in the last two decades, the world needs new interventions to prevent and treat TB. We, along with our partners, are tackling this challenge head on. Our goal is to accelerate the end of the TB epidemic through the development of a vaccine to help prevent TB for those at greatest risk for developing it and affordable, shorter, and simpler TB treatment regimens, including long-acting injectable agents, with an acceptable safety profile.
The biology of TB disease
TB is caused by Mycobacterium tuberculosis (Mtb) and spread from person to person by air, e.g., by spending extended time together in a single room or poorly ventilated space. TB typically affects the lungs but can affect almost any part of the body.
Most people do not get ill following infection with Mtb – referred to as latent TB – and many seem to clear or contain the infection. However, Mtb-infected people can progress to active TB disease either quickly or long after infection – approximately one in thirty infected people develop TB disease within two years of infection. People with a weakened immune system, e.g., malnourished people, people living with HIV, and people taking immune suppressing medications, as well as people with preexisting lung disease or with diabetes, are more likely to progress to active TB. Once a person develops active TB disease, the typical symptoms (cough, fever, night sweats, weight loss) are non-specific and may be mild, leading to delays in diagnosis and prolonging the period of transmission.
The complex biology of the bacterium and the limited efficacy of existing TB drugs as monotherapy requires treatment with multiple drugs for six months or longer. This involves significant health system resources to appropriately support TB patients throughout treatment. Poor patient outcomes and development of drug-resistant TB result when support is inadequate. New drugs and shorter treatment regimens to improve outcomes and reduce transmission, as well as new vaccines, are urgently needed to reduce the incidence of TB.
Approach
Recent and ongoing TB vaccine trials & epidemiology studies
Bacillus Calmette-Guérin (BCG) is the only licensed TB vaccine and is given to babies in the first week of life in most LMICs to prevent severe forms of TB in infancy and childhood. However, a single dose of BCG in infancy does not prevent pulmonary TB in adolescents and adults. In order to assess whether a second dose of BCG vaccine (BCG revaccination) can prevent Mtb infection, Gates MRI conducted a Phase 2b BCG revaccination trial in 1,800 adolescents in South Africa. Children over the age of ten were given either a second dose of BCG or saline placebo and were followed to monitor for new Mtb infections. The trial found that BCG revaccination did not prevent Mtb infection, and that this intervention is unlikely to offer public health benefit.
In 2020, Gates MRI obtained a license from GSK for the further development of an investigational TB vaccine designated M72/AS01E for most LMICs.
The first M72/AS01E clinical trial initiated by Gates MRI, referred to as the MESA-TB trial, evaluated the safety and immunogenicity of the investigational vaccine in people living with HIV in South Africa. Trial results are now published and show that M72/AS01E had an acceptable safety profile and was immunogenic. This information allowed us to include people living with HIV in the M72/AS01E Phase 3 trial.
Gates MRI subsequently conducted a large TB epidemiological study spanning Bangladesh, Brazil, Democratic Republic of Congo, The Gambia, India, Indonesia, Kenya, Mozambique, Peru, The Philippines, South Africa, Uganda, Vietnam, and Zambia to assess the prevalence of Mtb infection in people 15 to 34 years of age (ClinicalTrials.gov ID NCT05190146). The goal of this study was to inform selection of high prevalence communities for inclusion in the Phase 3 trial, so that vaccine efficacy can be assessed efficiently.
In early 2024, Gates MRI initiated a large Phase 3 TB vaccine registration trial at 54 sites in five countries in Africa and Asia (Indonesia, Kenya, Malawi, South Africa, and Zambia). This trial is following approximately 20,000 trial participants for up to four years to assess the safety and efficacy of M72/AS01E for the prevention of pulmonary TB in adolescents and adults aged 15 through 44 (ClinicalTrials.gov ID NCT06062238). Interest in this trial in the communities where the trial is conducted has been robust. We enrolled approximately 20,000 participants in 13 months and are now following them for approximately four years, until 110 participants have been diagnosed with pulmonary TB among all participants. At that point, the trial will be unblinded to see whether M72/AS01E elicited protection from TB in participants who received the vaccine.
Recent and ongoing TB Treatment Trials
Gates MRI is a member of the Project to Accelerate New Treatments for Tuberculosis (PAN-TB) collaboration. This group of philanthropic, non-profit, and private sector organizations is working together to expedite the development of a pan-TB regimen: a novel TB regimen capable of treating nearly all TB patients, even those with drug-resistant forms, to enable a simpler “test and treat” paradigm. Within the collaboration, Gates MRI is responsible for the execution of the Phase 2b/2c clinical trials intended to evaluate promising new regimens constructed with TB drugs from the PAN-TB partners to identify the best regimen for subsequent Phase 3 evaluation, in close coordination and joint governance with the partners.
A pan-TB regimen that is expected to be significantly shorter than current standard TB treatments (2-3 months) may potentially increase cure rates in TB patients, resulting in less transmission of infection, and a reduced burden on health systems that treat TB patients. In turn, this may also permit more resources to be focused on finding the estimated 2.3 million cases of active TB that go undiagnosed and/or untreated every year. All these advancements could have the collective potential to achieve greater global health impact, with accelerated decline in TB disease burden that ultimately paves the path to eliminating TB.
The first Phase 2b/2c clinical trial executed by Gates MRI on behalf of the PAN-TB Collaboration partners launched in July of 2023 focused on a 2-stage evaluation of two promising new regimens with nonclinical evidence of treatment shortening potential (ClinicalTrials.gov ID NCT05971602). Based on interim results from Stage 1 reviewed in July 2024, the trial was stopped early as the treatment response was not commensurate with curing patients within 3 months as per the target regimen profile for the partnership.
Gates MRI is currently working to advance the next wave of promising new TB drug candidates through early clinical development for Phase 2 readiness (ClinicalTrials.gov ID: NCT07094932, NCT06707142) and with the Gates Foundation, partners from the TB Drug Accelerator, and the other PAN-TB partners to identify the next novel combination regimen candidates for evaluation in a Phase 2b/2c trial. As part of the next wave of regimen evaluation with the PAN-TB partners, development of long-acting injectable formulations of promising new TB drug candidates will be included, substantially increasing the possibility of finding new TB regimens to transform treatment and hasten the decline of TB.
2.4 Million
Cases of active TB undiagnosed and untreated every year
10.7 million
People are estimated to have developed active TB in 2024 alone
1.23 Million
People died from TB in 2024
