title: Programming the magnitude and persistence of antibody responses with innate immunity.
abstract: Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, Georgia 30329, USA.
authors.forename: Sudhir Pai
authors.initials: SP
authors.lastname: Kasturi
authors.forename: Ioanna
authors.initials: I
authors.lastname: Skountzou
authors.forename: Randy A
authors.initials: RA
authors.lastname: Albrecht
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Koutsonanos
authors.forename: Tang
authors.initials: T
authors.lastname: Hua
authors.forename: Helder I
authors.initials: HI
authors.lastname: Nakaya
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ravindran
authors.forename: Shelley
authors.initials: S
authors.lastname: Stewart
authors.forename: Munir
authors.initials: M
authors.lastname: Alam
authors.forename: Marcin
authors.initials: M
authors.lastname: Kwissa
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
authors.forename: John
authors.initials: J
authors.lastname: Steel
authors.forename: Joshy
authors.initials: J
authors.lastname: Jacob
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hogan
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Richard
authors.initials: R
authors.lastname: Compans
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology*; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D019344:Lactic Acid; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D008024:Ligands; D051193:Toll-Like Receptors; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid