A proteome-wide atlas of humoral immunity to Mycobacterium tuberculosis across the spectrum of disease.

Exposure to Mycobacterium tuberculosis (Mtb) leads to a spectrum of outcomes, from latent infection to active disease, but limited insight into protective immune correlates has hampered vaccine development. Using a proteome-wide Mtb microarray, we mapped antibody specificities across individuals with varying Mtb exposure, including humans with controlled latent tuberculosis infection, uncontrolled active TB, or that resist IGRA conversion as well as non-human primates with near sterilized Mtb infection following intravenous BCG. While current TB vaccine antigens were poorly immunogenic across most populations, striking overlap in antibody binding was observed to surface and secreted proteins, all associated with enhanced antibody functions and some also robustly targeted by T cells. Collectively, these data provide an atlas of antibody protein binding across the spectrum of Mtb infection, and further point to a handful of promising Mtb protein candidates to guide the design of antibody-based TB interventions aimed at mitigating disease globally.