Rational design of small molecules as vaccine adjuvants

Abstract

Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants.

Innate transcriptional effects by adjuvants on the magnitude, quality, and durability of HIV envelope responses in NHPs

“…[62][63][64] The TLR4 agonist, E6020, 65 or a TLR7 agonist was adsorbed with Env to alum. 22 Env was also administered with MF59, or an ANE modified to incorporate the TLR4 or 7 agonists. 59 NHPs also received Env plus pIC:LC, 66,67 or ISCOMs.…”

“…[11][12][13][14][15][16] Alum and oil-in-water emulsions provide platforms for combining additional components to enhance their potency. For example, Toll-like receptor 4 (TLR4) [17][18][19] and TLR7 agonists [20][21][22] have been used. Improvements in antibody and T-cell immunity with these adjuvants are due to activation of distinct innate pathways in various APCs or direct activation of B cells.…”

Beyond antigens and adjuvants: formulating future vaccines

“…Encapsulation of small-molecule adjuvants in polymer nanoparticles (47,48) or liposomes (16,49) has been shown to eliminate systemic exposure to these compounds, while enhancing accumulation and stimulation of draining LNs in mice and nonhuman primates (NHPs). Direct modifications to small molecules have also been used to alter adjuvant pharmacokinetics: "small-molecule immune potentiator" (SMIP) TLR7 agonists containing aluminum-binding phosphate groups were recently synthesized, which, when mixed with alum, become bound to the adjuvant, focusing their action in the muscle and muscle-draining LNs (50). Alum-binding SMIPs showed much less systemic dissemination/toxicity than their non-alum-binding parent compounds, while exhibiting much greater efficacy for promoting humoral immunity in mice.…”

Addition of a TLR7 agonist to an acellular pertussis vaccine enhances Th1 and Th17 responses and protective immunity in a mouse model

“…A number of studies have explored the use of TLR7 agonists (TLR7a) as vaccine adjuvants and have employed different strategies, including conjugating TLR7a to pathogen antigens or adsorption to alum, to optimize their immune stimulating effects, while minimizing toxicity [13][14][15]. Adsorption of the TLR7a to alum reduces its systemic circulation and excessive cytokine release into serum.…”