This study investigates the mechanisms by which vaccines induce long-lasting antibody responses. The authors developed a nanoparticle-based vaccine that contains antigens and Toll-like receptor (TLR) ligands, specifically TLR4 and TLR7, encapsulated in poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles. They found that immunization with nanoparticles containing both TLR ligands (PLGA(MPL+R837)) induced synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with a single TLR ligand. This resulted in enhanced persistence of germinal centers (GCs) and plasma cell responses, which lasted for over 1.5 years. The mechanism was attributed to the activation of both dendritic cells (DCs) and B cells via TLRs, as well as T-cell help. The vaccine also enhanced the magnitude and quality of antigen-specific memory CD4+ and CD8+ T cells, leading to robust protection against lethal influenza virus strains in mice and rhesus macaques. The study highlights the importance of combining TLR ligands and antigens on separate particles for optimal immune responses.This study investigates the mechanisms by which vaccines induce long-lasting antibody responses. The authors developed a nanoparticle-based vaccine that contains antigens and Toll-like receptor (TLR) ligands, specifically TLR4 and TLR7, encapsulated in poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles. They found that immunization with nanoparticles containing both TLR ligands (PLGA(MPL+R837)) induced synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with a single TLR ligand. This resulted in enhanced persistence of germinal centers (GCs) and plasma cell responses, which lasted for over 1.5 years. The mechanism was attributed to the activation of both dendritic cells (DCs) and B cells via TLRs, as well as T-cell help. The vaccine also enhanced the magnitude and quality of antigen-specific memory CD4+ and CD8+ T cells, leading to robust protection against lethal influenza virus strains in mice and rhesus macaques. The study highlights the importance of combining TLR ligands and antigens on separate particles for optimal immune responses.