PRECISE-TBM

The challenge

Although tuberculosis is mostly a disease of the lungs, the bacterium that causes TB (Mycobacterium tuberculosis, Mtb) can also infect brain tissues. This can lead to a potentially deadly form of meningitis, tuberculous meningitis (TBM). The condition particularly affects children, leading to either death or long-term neurological conditions in around half of those who are successfully diagnosed and put on TB treatment. If the brain is infected with Mtb and the patient is not treated, it will certainly result in death.

One of the biggest challenges in TBM care is diagnosis. Symptoms are shared with multiple other conditions and there is no simple diagnostic test for TBM. It may take up to six visits to health facilities before a diagnosis is made, leading to significant delays in treatment initiation.

The project

The PRECISE-TBM project is building on previous EDCTP-funded research to develop a rapid diagnostic test for TBM suitable for use in sub-Saharan African settings.

In a previous EDCTP project, members of the PRECISE-TBM team discovered that the presence of three proteins (known as VEGF, MPO, and IFN-g) in cerebrospinal fluid (CSF) samples was highly indicative of TBM. This led to the development of a prototype lateral flow test that could provide diagnostic information within 15 minutes.

The team has subsequently worked with a South African biotech company to transfer the test onto a new, more sensitive biosensor platform. In addition, it has identified a five-protein signature characteristic of TBM in blood samples, which could eliminate the need to collect CSF samples. 

The PRECISE-TBM project is progressing both the CSF and blood-based biomarker technologies. The new biosensor version of the CSF-based test will be evaluated in a clinical study in South Africa, Zambia and Zimbabwe. The study will recruit more than 500 children with presumed meningitis and compare the performance of the CSF-based test with the gold-standard diagnostic assessment. In parallel, the blood-based biomarker test is being refined, and its performance is being evaluated using stored samples. It will then be transferred onto the biosensor platform and evaluated alongside the CSF-based tests.

The project is also conducting studies to assess a potential issue with the three-protein signature. IFN-g is an important component of the host immune response to Mtb. However, the ability to generate IFN-g responses varies within a population, and some people are at risk of Mtb infections because they are less able to produce IFN-g. This could potentially lead to a false-negative TBM test result. 

The project is therefore collecting data on IFN-g responses in blood and CSF samples during the trial, to determine whether participants have antibodies against IFN-g (which block its action) or carry genetic variants leading to low IFN-g responses. It will then assess the implications of these findings for the reliability of test results.

Impact

The PRECISE-TBM project could have a major impact on the care of patients with TBM. It will:

• Generate clinical data on the performance of the three-protein CSF-based test.
• Create a potentially more accessible blood-based test and compare its performance with the CSF tests.
• Determine whether variation in IFN-g responses might affect the reliability of test results.

A rapid point-of-care test for TBM could transform the diagnostic journey for TBM patients, most of them children, who currently face multiple visits to health facilities before receiving a diagnosis and being started on treatment.