Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but our research demonstrates that the yellow fever vaccine activates DCs via multiple TLRs to stimulate persistent antibody responses. We thus designed synthetic nanoparticles that encapsulate specific combinations of TLR-ligands plus antigen.  In mice, these particles induced a synergistic enhancement in the persistence of germinal centers and of plasma-cell responses, relative to particles containing ligands against a single TLR¹. In macaques, these nanoparticle-based adjuvants, and in particular a novel synthetic TLR7/8 ligand (3M-052) induced robust and persistent antibody responses and long-lived bone marrow plasma cell responses which continued unabated for at least 70 weeks². Based on these results, 3M-052 is now being tested in phase I clinical trials as a vaccine adjuvant in HIV vaccines. In related work, we have used a systems approach to define a transcriptional signature that predicts the durability of antibody responses to several vaccines, including the seasonal influenza vaccine, AS03-adjuvanted H5N1 vaccine, Pfizer-BioNTech COVID mRNA vaccine, and the malaria RTS, S vaccine. We are currently exploring the underlying biology of this transcriptional signature on the durability of antibody responses.