Nanobody-based diagnostics for tuberculosis

The National Institute of Allergy and Infectious Diseases awarded Oregon Health & Science University $731,581 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop nanobody-based diagnostics for tuberculosis.

The project addresses the clinical challenge of TB diagnosis in resource-limited settings. Current point-of-care tests lack sufficient sensitivity, and laboratory-based diagnostics require complex infrastructure unavailable in low-resource regions where most TB cases occur. Mycobacterium tuberculosis produces multiple antigens that vary by disease stage, bacterial burden, infection site, and comorbidities such as HIV or diabetes; effective diagnosis requires simultaneous detection across this antigen diversity. The recipient will engineer a diagnostic platform using nanobodies—small, single-domain antibodies derived from camelids—which offer high specificity and affinity, exceptional thermal stability, low production cost, and straightforward engineering. The platform is designed to detect multiple TB antigens simultaneously to capture disease presentation across the full spectrum of active TB. The recipient has already generated nanobodies against key TB antigens and demonstrated their high sensitivity in biospecimens.

Performance occurs at Portland, Oregon 97239. The award period runs from September 1, 2026, through August 31, 2027. This is a project grant, the standard assistance type for investigator-initiated research under the NIAD program.

Abstract

Tuberculosis (TB) is primarily a lung disease and remains one of the world's most urgent health threats, causing more deaths annually than any other infectious disease. In 2023, an estimated 10.8 million people developed active TB, resulting in 1.25 million deaths. Alarmingly, nearly 25% of these cases were undiagnosed, driving ongoing transmission, chronic lung damage and deaths. If not addressed, TB is projected to cause tens of millions of deaths and trillions of dollars in economic loss, and widespread chronic lung disease. Drug-resistant TB further worsens the crisis, accounting for 29% of deaths from antimicrobial resistance, lung d and threatening to reverse decades of progress. Current diagnostics are insufficient, especially in low-resource settings where most TB cases occur. Existing point-of-care (POC) tests lack sensitivity and laboratory-based tests require complex infrastructure, urging the who to call for the development of POC TB diagnostics that are effective across the full spectrum of active TB disease presentations. The diagnostic challenges, especially for POC, arise from the biological complexity of TB. Unlike other pathogens, MTB does not release a single dominant biomarker; instead, IT produces multiple antigens that vary depending on disease stage, bacterial burden, site of infection, and CO-morbidities such as HIV or diabetes. Therefore, an effective diagnostic must detect multiple antigens simultaneously to capture the full diversity of TB disease. To meet this need, we propose a nanobody (NB)-based diagnostic platform. NBS, small, single-domain antibodies derived from camelids, offer high antigen specificity and affinity, exceptional stability, low production cost, and ease of engineering, making them especially suitable for use in low-resource settings. Using our established platform, we have already generated NBS against key TB antigens and showed their high sensitivity in biospecimen, showing their strong diagnostic potential. In aim 1, we will strategically expand our NB repertoire by developing NBS against MTB antigens already proven in the literature to be present in patient blood and urine samples. In parallel, we will analyse clinical specimens from TB patients to discover the antigens most consistently detected during active disease, then generate NBS that specifically target these proteins. This work will allow US to select the best diagnostic targets to ensure our test can detect TB in a wide range of patients. In aim 2, we will enhance these NBS to make them even more powerful. Using advanced engineering techniques, we will link NBS together so they can attach to different parts of the same antigen at the same time, making detection much more sensitive. This will help ensure that our test can identify TB even when antigen levels are very low. In aim 3, we will combine these engineered NBS into a single test that can detect multiple TB antigens in patient biospecimens. This "multiplexed" approach is key to capturing the full range of TB cases, including those that current tests miss. We will test this new diagnostic method using samples from real patients to make sure IT works across different forms of TB. By the end of this project, we aim to create a strong foundation for a low-cost, easy-to-use TB test that can be deployed worldwide, improving early detection, saving lives, and helping control the spread of this deadly disease.