The use of Toll-like receptor 7/8 agonists as vaccine adjuvants

Abstract

Small molecule Toll-like receptor (TLR) 7/8 agonists have demonstrated potential as vaccine adjuvants, since they directly activate APCs and can enhance both humoral and cellular immune responses, especially Th1 responses. Although the natural ligands for TLR7 and TLR8 are ssRNA, the vast majority of vaccine studies performed thus far have been performed with synthetic small molecule imidazoquinolines, such as imiquimod and resiquimod. Despite the approved clinical use of the topical TLR7 agonist, imiquimod (Aldara^® Imiquimod 5% cream; 3M, MN, USA), for external genital warts, superficial basal cell carcinoma and actinic keratosis, no vaccines using TLR7, TLR8 or TLR7/8 agonists have progressed beyond early-phase clinical studies thus far. This review will highlight the nonclinical and clinical studies that indicate promise for TLR7/8 ligands as vaccine adjuvants, reasons for inconsistent results thus far, problems with current technology and potential paths forward for TLR7/8 agonists as vaccine adjuvants.

Keywords::

• Aldara^®
• dendritic cells
• imidazoquinolines
• imiquimod
• resiquimod (R-848)
• TLR7
• TLR8

Acknowledgements

In regard to the 3M-052 data presented here, the authors thank David Brandwein and Joe Beaurline for preparation of the formulations, Dave Ehresman and Al Eveland for 3M-052 serum quantitation and Karen Johnson for serum resiquimod measurement. The authors especially thank Dmitri Smirnov, Paul Wightman, Joshua Schmidt and Minghua Dai for the 3M-052 vaccine studies.

Financial & competing interests disclosure

The authors are employees of 3M and are beneficiaries of the 3M employee stock plan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.