Evaluation of novel synthetic TLR7/8 agonists as vaccine adjuvants
Autor: | Jory R. Baldridge, Jay T. Evans, Yufeng Li, Alyson J. Smith, Daniel Larocque, Hélène G. Bazin, Julien R. St-Jean |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Agonist Pyridines Swine medicine.drug_class medicine.medical_treatment Adaptive Immunity CD8-Positive T-Lymphocytes Biology Article Proinflammatory cytokine 03 medical and health sciences chemistry.chemical_compound Adjuvants Immunologic Antigen Interferon medicine Animals Humans Vaccines General Veterinary General Immunology and Microbiology Imidazoles Public Health Environmental and Occupational Health Antibody titer Dendritic Cells Acquired immune system Imidazoquinoline 030104 developmental biology Infectious Diseases Toll-Like Receptor 7 chemistry Toll-Like Receptor 8 Immunology Quinolines Cytokines Molecular Medicine Adjuvant medicine.drug |
Zdroj: | Vaccine. 34:4304-4312 |
ISSN: | 0264-410X |
Popis: | Small-molecule adjuvants that boost and direct adaptive immunity provide a powerful means to increase the effectiveness of vaccines. Through rational design several novel imidazoquinoline and oxoadenine TLR7/8 agonists, each with unique molecular modifications, were synthesized and assessed for their ability to augment adaptive immunity. All agonists bound human TLR7 and TLR8 and induced maturation of both human mDCs and pDCs. All agonists prompted production of type I interferon and/or proinflammatory cytokines, albeit with varying potencies. In most in vitro assays, the oxoadenine class of agonists proved more potent than the imidazoquinolines. Therefore, an optimized oxoadenine TLR7/8 agonist that demonstrated maximal activity in the in vitro assays was further assessed in a vaccine study with the CRM197 antigen in a porcine model. Antigen-specific antibody production was greatly enhanced in a dose dependent manner, with antibody titers increased 800-fold compared to titers from pigs vaccinated with the non-adjuvanted vaccine. Moreover, pigs vaccinated with antigen containing the highest dose of adjuvant promoted a 13-fold increase in the percentage of antigen-specific CD3(+)/CD8(+) T cells over pigs vaccinated with antigen alone. Together this work demonstrates the promise of these novel TLR7/8 agonists as effective human vaccine adjuvants. |
Databáze: | OpenAIRE |
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