The purpose of this BAA is to renew the NIAID Adjuvant Discovery Program that supports the identification and characterization of novel, effective and safe vaccine adjuvants. The process of discovery new adjuvants through this program must include each of the following areas of research: (1) Identification of novel adjuvant candidates using high throughput (HTS) approaches and validation that lead compounds stimulate human cells; (2) determination of the mechanism of action of select lead compounds, including the identification of the receptor(s) the adjuvant candidates work through and/or the cellular signaling pathways they activate; (3) optimization of lead adjuvant candidates through formulation and medicinal chemistry, guided by structure-activity relationship (SAR) studies; and (4) verification of the efficacy of lead compounds as vaccine adjuvants in vivo in an animal model. Offerors are encouraged, but not required, to evaluate lead adjuvant candidates in model systems of vulnerable populations (e.g., newborns, elderly or immunocompromised individuals). Lead adjuvant candidates identified under a contract project may also be tested with different vaccine platforms, including nucleic acid-based vaccines. Not only the shortterm efficacy, but also the durability of the immune response induced by the adjuvanted vaccine must be evaluated.