TLR Agonists as Vaccine Adjuvants

Abstract

Small molecule TLR7/8 agonists have demonstrated great potential as vaccine adjuvants, since they quantitatively and qualitatively enhance both humoral and cellular immune responses. However, most small molecule TLR agonists evaluated thus far as vaccine adjuvants are highly soluble and have a propensity to rapidly disperse away from the vaccination site, resulting in decreased efficacy and increased systemic adverse effects. Intense effort and progress has been made to increase their ability to maintain close proximity to antigen at the administration site. Here, we will discuss three vaccine approaches utilizing small molecule TLR7/8 agonists as vaccine adjuvants. These approaches are designed to improve the adjuvanticity and to reduce the potential for systemic adverse events associated with these small molecule TLR7/8 agonists when used as vaccine adjuvants. One approach utilizes the TLR7/8 agonist resiquimod gel as a topically applied adjuvant at the vaccination site. The other two approaches utilize novel TLR7/8 agonists in a conventional vaccine format where the adjuvant and antigen are administered together. These novel TLR7/8 agonists are lipid modified or chemically modified for conjugation to antigen—all three approaches are designed to promote retention of the TLR7/8 agonists at the administration site in order to maintain their spatial and temporal proximity to the antigen, resulting in enhanced immune responses and reduced systemic adverse effects.