Vaccines are a powerful defense against infectious diseases, and the advent of successful vaccines against diverse pathogens has saved millions of lives to date. However, a number of diseases relevant to the military have remained unsolved challenges for vaccine development, including malaria, tuberculosis, HIV, and Ebola. Protein vaccines do not typically elicit an immune response on their own, and must combined with adjuvants, compounds that provide inflammatory cues or promote the immune response to a co-administered antigen. Adjuvant design is made challenging by the need to strongly drive specific aspects of the immune response while maintaining a rigorous safety profile for administration to healthy recipients. Nanotechnology-based approaches that target vaccine adjuvants or immunomodulators to lymph nodes have the capacity to enhance both the potency and safety of vaccines, by focusing adjuvant activity in tissues where immune responses are initiated and avoiding systemic exposure. In a similar manner, the targeting of immunomodulators or antimicrobial compounds to lymphoid tissues or specific critical leukocyte populations can be envisioned to enhance the therapeutic clearance of infections. Project 1.6 proposes to develop two platform technologies that safely and efficiently promote immune responses in the vaccination and therapeutic settings: lymph node targeting amphiphile-adjuvants and immune-targeting amphiphilic ligand-coated metal nanoparticles. These two approaches are ideally suited to targeting adjuvant compounds to lymphoid tissues and immunomodulators to immune cells during infection, respectively. In preliminary studies performed with colleagues at the US Army Medical Research Institute of Infectious Diseases (USAMRIID), promising results have been obtained in mouse models of Ebola virus infection using lymph node targeting adjuvants. Nanotechnology-based adjuvants/immunomodulators focusing particularly on enhancing affinity maturation and cytotoxic T-cell induction will be developed, and the research team will partner with USAMRIID to apply these technologies to Ebola and other vaccines.