A nanoparticle-based vaccine containing antigens and Toll-like receptor (TLR) ligands MPL and R837 was developed to enhance antibody responses. This vaccine, composed of poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, induced synergistic increases in antigen-specific, neutralizing antibodies compared to vaccines with single TLR ligands. The vaccine enhanced the persistence of germinal centers (GCs) and plasma cell responses, which lasted over 1.5 years in lymph nodes. It also increased the affinity of antigen-antibody binding and neutralizing antibody titers, providing robust protection against lethal influenza virus strains in mice and rhesus macaques. The vaccine's effectiveness was attributed to the activation of dendritic cells (DCs) and B cells via TLRs, as well as T-cell help. The combined TLR4 and TLR7 stimulation enhanced the GC pathway, leading to the generation of memory B cells and long-lived plasma cells. The vaccine also enhanced antigen-specific CD4+ and CD8+ T cell responses, contributing to protective immunity. In non-human primates, the vaccine showed dose sparing effects, with lower antigen doses achieving similar protective responses when combined with the adjuvant. The vaccine's design, which resembles a virus in size and composition, offers a universal platform for vaccine development against pandemics and emerging infections. It leverages innate immunity to program persistent antibody responses, demonstrating the potential of nanoparticle-based vaccines in enhancing immunological memory and protection against infectious diseases.A nanoparticle-based vaccine containing antigens and Toll-like receptor (TLR) ligands MPL and R837 was developed to enhance antibody responses. This vaccine, composed of poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, induced synergistic increases in antigen-specific, neutralizing antibodies compared to vaccines with single TLR ligands. The vaccine enhanced the persistence of germinal centers (GCs) and plasma cell responses, which lasted over 1.5 years in lymph nodes. It also increased the affinity of antigen-antibody binding and neutralizing antibody titers, providing robust protection against lethal influenza virus strains in mice and rhesus macaques. The vaccine's effectiveness was attributed to the activation of dendritic cells (DCs) and B cells via TLRs, as well as T-cell help. The combined TLR4 and TLR7 stimulation enhanced the GC pathway, leading to the generation of memory B cells and long-lived plasma cells. The vaccine also enhanced antigen-specific CD4+ and CD8+ T cell responses, contributing to protective immunity. In non-human primates, the vaccine showed dose sparing effects, with lower antigen doses achieving similar protective responses when combined with the adjuvant. The vaccine's design, which resembles a virus in size and composition, offers a universal platform for vaccine development against pandemics and emerging infections. It leverages innate immunity to program persistent antibody responses, demonstrating the potential of nanoparticle-based vaccines in enhancing immunological memory and protection against infectious diseases.