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Two <jats:italic>Leishmania<\/jats:italic> proteins\u2014nucleoside hydrolase and a sterol 24\u2010c\u2010methyltransferase, each of which are protective in animal models of VL when properly adjuvanted\u2014 were produced as a single recombinant fusion protein NS (LEISH\u2010F3) for ease of antigen production and broad coverage of a heterogeneous major histocompatibility complex population. When formulated with glucopyranosyl lipid A\u2010stable oil\u2010in\u2010water nanoemulsion (GLA\u2010SE), a Toll\u2010like receptor 4 T<jats:sub>H<\/jats:sub>1 (T helper 1) promoting nanoemulsion adjuvant, the LEISH\u2010F3 polyprotein induced potent protection against both <jats:italic>L. donovani<\/jats:italic> and <jats:italic>L. infantum<\/jats:italic> in mice, measured as significant reductions in liver parasite burdens. A robust immune response to each component of the vaccine with polyfunctional CD4 T<jats:sub>H<\/jats:sub>1 cell responses characterized by production of antigen\u2010specific interferon\u2010\u03b3, tumor necrosis factor and interleukin\u20102 (IL\u20102), and low levels of IL\u20105 and IL\u201010 was induced in immunized mice. We also demonstrate that CD4 T cells, but not CD8 T cells, are sufficient for protection against <jats:italic>L. donovani<\/jats:italic> infection in immunized mice. Based on the sum of preclinical data, we prepared GMP materials and performed a phase 1 clinical study with LEISH\u2010F3+GLA\u2010SE in healthy, uninfected adults in the United States. The vaccine candidate was shown to be safe and induced a strong antigen\u2010specific immune response, as evidenced by cytokine and immunoglobulin subclass data. 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