Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants

Abstract

Adjuvants are used to maximize the potency of vaccines by enhancing immune reactions. Components of adjuvants include pathogen-associated molecular patterns (PAMPs) and damage-associate molecular patterns (DAMPs) that are agonists for innate immune receptors. Innate immune responses are usually activated when pathogen recognition receptors (PRRs) recognize PAMPs derived from invading pathogens or DAMPs released by host cells upon tissue damage. Activation of innate immunity by PRR agonists in adjuvants activates acquired immune responses, which is crucial to enhance immune reactions against the targeted pathogen. For example, agonists for Toll-like receptors have yielded promising results as adjuvants, which target PRR as adjuvant candidates. However, a comprehensive understanding of the type of immunological reaction against agonists for PRRs is essential to ensure the safety and reliability of vaccine adjuvants. This review provides an overview of the current progress in development of PRR agonists as vaccine adjuvants, the molecular mechanisms that underlie activation of immune responses, and the enhancement of vaccine efficacy by these potential adjuvant candidates.

Keywords: PAMP; TLR; adjuvant; innate immunity; pattern recognition receptor (PRR).

Figure 1

Adjuvant candidates and their respective receptors. TLR4 and TLR5 are expressed on the cell surface, while TLR3, TLR4, TLR7, TLR8, and TLR9 are expressed in endosomes. TLR4, TLR5, TLR7, TLR8, and TLR9 initiate signaling through the MyD88 pathway to activate NF-κB, which induces the production of proinflammatory cytokines. Activated Syk elicits the production of proinflammatory cytokines through the NF-κB signaling pathway. RIG-1 and MDA-5 are intracellular nucleic acid sensors that induce both proinflammatory cytokines and type-1 interferons via MyD88 and IRF signaling pathways. cGAS produces cGAMP that activates the cGAS-stimulator STING located on the ER to induce production of proinflammatory cytokines through the NF-κB signaling pathway. Inflammasomes (AIM2, NLRP1, NLRP3, and NLRC4) cleave pro-caspase 1 into caspase 1 that subsequently cleaves pro-IL-1β, pro-IL-18, and Gasdermin D into their mature forms, respectively. N-terminal Gasdermin D oligomerizes to form pores, inducing pyroptosis. Blue text represents adjuvant candidates discussed in this review.