A nanoliposome delivery system to synergistically trigger TLR4 AND TLR7.
BACKGROUND
Recent reports that TLR4 and TLR7 ligands can synergistically trigger Th1 biased immune responses suggest that an adjuvant that contains both ligands would be an excellent candidate for co-administration with vaccine antigens for which heavily Th1 biased responses are desired. Ligands of each of these TLRs generally have disparate biochemical properties, however, and straightforward co-formulation may represent an obstacle.


RESULTS
We show here that the TLR7 ligand, imiquimod, and the TLR4 ligand, GLA, synergistically trigger responses in human whole blood. We combined these ligands in an anionic liposomal formulation where the TLR7 ligand is in the interior of the liposome and the TLR4 ligand intercalates into the lipid bilayer. The new liposomal formulations are stable for at least a year and have an attractive average particle size of around 140 nm allowing sterile filtration. The synergistic adjuvant biases away from Th2 responses, as seen by significantly reduced IL-5 and enhanced interferon gamma production upon antigen-specific stimulation of cells from immunized mice, than any of the liposomal formulations with only one TLR agonist. Qualitative alterations in antibody responses in mice demonstrate that the adjuvant enhances Th1 adaptive immune responses above any adjuvant containing only a single TLR ligand as well.


CONCLUSIONS
We now have a manufacturable, synergistic TLR4/TLR7 adjuvant that is made with excipients and agonists that are pharmaceutically acceptable and will have a straightforward path into human clinical trials.
Christopher B
CB
Fox
Sandra J
SJ
Sivananthan
Malcolm S
MS
Duthie
Julie
J
Vergara
Jeffrey A
JA
Guderian
Elliot
E
Moon
David
D
Coblentz
Steven G
SG
Reed
Infectious Disease Research Institute (IDRI), Seattle, WA, USA. dcarter@idri.org.
Darrick
D
Carter
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000077271:Imiquimod; D008055:Lipids / Q000008:administration & dosage / Q000494:pharmacology; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D008055:Lipids; D008081:Liposomes; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D000077271:Imiquimod