Breaking the deadlock in antigen discovery for Leishmania vaccines

Despite the global burden of leishmaniasis, no licensed human vaccine exists. Vaccine antigens are typically based on in silico predictions or their immunogenicity in animal models and cured patients. T cell epitopes have only been mapped for fewer than 2% of over 8000 Leishmania proteins, with only ten proteins tested in clinical trials. Whether infected human phagocytes naturally present such antigens early on during infection, and prior to the onset of parasite-induced regulatory mechanisms, is unknown. We discuss why this is critical to the induction of protective immunity and argue that antigen availability can conclusively guide and accelerate vaccine candidate discovery. Here, emerging technologies, including immunopeptidomics, single-cell multiomics, and T cell receptor repertoire mapping, offer transformative opportunities to redefine Leishmania antigen discovery.