Tuberculosis (TB) is a leading cause of death in children, with an estimated 1 million children affected, and more than 200,000 deaths in children yearly due to TB. HIV coinfection has been estimated to contribute to more than 35% of TB-related deaths in children in Africa, making the collision of the HIV and TB epidemics one of the most lethal to date. Both HIV infection as well as HIV-exposure in utero, among HIV-exposed but uninfected (HEU) children, have been linked to higher risks for the development of TB among young children. Failures to prevent TB disease and devastation has been attributed to the lack of an effective vaccine as well as our inability to diagnose children under the age of 5 due to the difficulty in obtaining sputum and the paucibacillary nature of the disease in young children. Thus, an inexpensive biomarker-based diagnostic test tailored for pediatric TB using non-sputum samples that could be used at the point of care in resource-limited settings could profoundly improve TB treatment and prevent deaths in children, especially in those under 5 years of age. While Mtb-specific antibody titer-based diagnostics have performed poorly in the past, due to the inability of accurately distinguishing between active TB disease from latent TB infection (LTBI), recent data from our group has shown that Mtb-specific antibody glycosylation shifts significantly across disease states. Moreover, this antigen-specific antibody glycosylation approach reliably classifies individuals into active and latent disease states across HIV infection status, across geographies and can even distinguish recent Typhoid infection among children in endemic areas. Based on these observations, a simple binding-based assay was developed that can rapidly, sensitively, and specifically detect changes in Mtb-specific antibody glycosylation from a small sample volume offering an opportunity for the first time to develop an antigen-specific antibody glycosylation diagnostic for pediatric TB from a microliter-scale sample. Given that HIV+, HEU, or unexposed children may target distinct Mtb antigens, here we have assembled a multi-disciplinary team and program termed FASTER-Kids (Fc Antibody Signatures for TubERculosis in children) that will: 1) Define the landscape of Mtb-specific antibody glycosylation responses that distinguish children with TB, 2) Develop a point-of-care test that will rapidly capture these specific antibody responses and glycosylation changes from microliters of blood. Ultimately, this collaborative structure will enable the iterative improvement and development of this simple, rapid, inexpensive diagnostic to manage TB infection in young children.
Based on accumulating data pointing to highly significant shifts in TB-specific antibody glycosylation across latent and active TB disease, the goal of this proposal is to develop an inexpensive, simple, reliable TB-specific antibody-based point-of-care diagnostic to manage TB disease in children under the age of 5.
