Leveraging antibody-omics to prevent and detect TB in children affected by HIV

ABSTRACT One million children develop tuberculosis (TB) each year and TB is the leading cause of death among children with HIV. Novel strategies to diagnose and prevent pediatric TB are urgently needed, but progress has been hindered by poor sensitivity of current microbiologic and immunologic diagnostic tools, as well as an unclear understanding of immune correlates of TB protection. We have led clinical and translational research studies to elucidate humoral immune responses to TB in children and adults and have optimized a multiparameter high- throughput assay to characterize detailed antigen-specific antibody Fc features that guide both innate and adaptive TB immune responses. We propose to leverage specimen repositories from well-characterized clinical pediatric cohorts from Kenya, South Africa, India, and a multi-center IMPAACT study to define antibody Fc features associated with protection from Mycobacterium tuberculosis (Mtb) infection among infants with and without maternal HIV exposure (Aim 1) and identify biomarkers for active TB and Mtb infection as compared to Mtb-uninfected healthy controls (Aim 2). We hypothesize that an IgM-based signature detected in early infancy will be associated with protection from Mtb infection, and that we will discover unique Mtb-specific antibody Fc glycan profiles among children with TB disease. The results of this study will have significant public health implications for children affected by HIV in TB-endemic settings, through advancing our knowledge of Mtb- specific humoral immunity that can be harnessed for innovative public health strategies, including new maternal and infant vaccines, monoclonal antibody development, and point-of-care (POC) testing for Mtb infection and TB disease.