Breaking the deadlock in antigen discovery for Leishmania vaccines

Highlights
Over 1 billion people live in areas endemic for leishmaniasis, yet no licensed vaccine for human use exists, nor are there any vaccine trials ongoing.

Despite decades of antigen discovery, less than 2% of over 8000 Leishmania proteins have mapped T cell epitopes, with only ten antigens reaching clinical trials.

Driven by the overwhelming proteome size of the Leishmania parasite, the vaccine pipeline relied on immunodominant antigens from treated patients, overlooking potentially discordant major histocompatibility complex presentation during early infection stages that are critical for protective immunity.

Emerging tools—immunopeptidomics, single-cell multiomics, and T cell receptor repertoire mapping—now enable direct, unbiased discovery of naturally presented epitopes in clinical studies.

Integrating these technologies with controlled human infection models can fast-track and redefine antigen selection to accelerate subunit vaccine development.

Abstract
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.