Publication Date:
2011-02-26
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057367/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057367/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kasturi, Sudhir Pai -- Skountzou, Ioanna -- Albrecht, Randy A -- Koutsonanos, Dimitrios -- Hua, Tang -- Nakaya, Helder I -- Ravindran, Rajesh -- Stewart, Shelley -- Alam, Munir -- Kwissa, Marcin -- Villinger, Francois -- Murthy, Niren -- Steel, John -- Jacob, Joshy -- Hogan, Robert J -- Garcia-Sastre, Adolfo -- Compans, Richard -- Pulendran, Bali -- HHSN266200700006C/PHS HHS/ -- HHSN266200700010C/PHS HHS/ -- N01 AI50025/AI/NIAID NIH HHS/ -- R01 AI048638/AI/NIAID NIH HHS/ -- R01 AI048638-07/AI/NIAID NIH HHS/ -- R01 AI048638-08/AI/NIAID NIH HHS/ -- R01 DK057665/DK/NIDDK NIH HHS/ -- R01 DK057665-09/DK/NIDDK NIH HHS/ -- R01 DK057665-10/DK/NIDDK NIH HHS/ -- R01 DK057665-11/DK/NIDDK NIH HHS/ -- R01 DK057665-12/DK/NIDDK NIH HHS/ -- R01 DK057665-13/DK/NIDDK NIH HHS/ -- R01DK057665/DK/NIDDK NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 AI048638-09A1/AI/NIAID NIH HHS/ -- R37 AI048638-10/AI/NIAID NIH HHS/ -- R37 AI048638-11/AI/NIAID NIH HHS/ -- R37AI48638/AI/NIAID NIH HHS/ -- R56 AI048638/AI/NIAID NIH HHS/ -- R56 AI048638-09/AI/NIAID NIH HHS/ -- U01AI070469/AI/NIAID NIH HHS/ -- U19AI057266/AI/NIAID NIH HHS/ -- U19AI090023/AI/NIAID NIH HHS/ -- U54AI057157/AI/NIAID NIH HHS/ -- U54AI57158/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Feb 24;470(7335):543-7. doi: 10.1038/nature09737.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Emory University, Atlanta, Georgia 30329, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350488" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antibodies, Neutralizing/biosynthesis/*immunology
;
Antibodies, Viral/biosynthesis/*immunology
;
Antibody Formation/*immunology
;
Dendritic Cells/cytology/immunology
;
Hemagglutinin Glycoproteins, Influenza Virus/immunology
;
Immunity, Innate/*immunology
;
Immunologic Memory/*immunology
;
Influenza A Virus, H1N1 Subtype/immunology
;
Influenza A Virus, H5N1 Subtype/immunology
;
Influenza Vaccines/administration & dosage/*immunology
;
Lactic Acid
;
Ligands
;
Lymph Nodes/cytology/immunology
;
Lymphocyte Activation
;
Macaca mulatta/immunology/virology
;
Mice
;
Mice, Inbred BALB C
;
Mice, Inbred C57BL
;
Nanoparticles/administration & dosage
;
Plasma Cells/cytology/immunology/metabolism
;
Polyglycolic Acid
;
T-Lymphocytes/immunology
;
Toll-Like Receptors/immunology/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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