Tuberculosis (TB) is the leading infectious cause of death worldwide, and is caused by the slow growing bacterium Mycobacterium tuberculosis (Mtb). Because the time between infection and disease can be long – years or even decades – a major challenge for public health is knowing who is at risk for becoming ill so that they can be treated with prophylactic drugs. The standard of care for identifying infected individuals in most parts of the world is the tuberculin skin test (TST), which was originally developed in 1886. In recent years, a more modern, quantitative test was developed, called the interferon-gamma release assay (IGRA), where immune responses to Mtb proteins provide evidence of infection. However, peculiarly, a significant proportion of highly exposed individuals worldwide perpetually test negative in both these tests – raising the possibility that these individuals are either “resistant” to Mtb infection or perhaps the tests are failing to detect their infection.

The present work, published in Nature Medicine, aimed to address this very issue. In a collaborative study between the Ragon Institute of Mass General, MIT, and Harvard, Case University, the University of Washington, and the study staff at the Uganda-CWRU Research Collaboration clinic in Kampala, Uganda, the authors asked a simple question: Do individuals that live in a household with active MTB patients but never convert their TST or IGRA have any evidence of infection with Mtb? The team took a broad immunologic approach by looking at immune responses to Mtb-specific proteins that would not be captured by TST or IGRA. Indeed, they found robust immunity to Mtb – dissimilar to that found in traditionally detectable Mtb infection – but unequivocally demonstrating that these individuals had certainly mounted a response to this pathogen, and likely had been infected with Mtb. 

These findings have several immediate implications. First, the standard in public health tests clearly fails to capture a significant proportion of the exposed populations. In fact, the current study suggests that even those who test negative on the standard tests may be infected with Mtb and deserve further consideration for treatment. Second, clinical trials of new TB vaccines selectively use IGRA-negative participants and use IGRA conversion as a measure of success or failure of the vaccine. Clearly, some of these IGRA-negative individuals may be infected and certainly possess immunity to Mtb – potentially confounding any future immunologic work on vaccine immunity/efficacy. Finally, given that it is unclear whether these individuals are infected or have cleared the infection, the unique immunity elicited in these individuals could point to immunological functions that may control and even eradicate Mtb more effectively. Thus, as we forge into an era of aggressive Mtb-vaccine development, the results captured in this study challenge current dogmas on Mtb exposure and potentially point to unexpected anti-microbial immune functions that may guide next generation vaccine design.