Cyclic di‐nucleotides: new era for small molecules as adjuvants

Abstract

SummaryThe implementation of vaccination as an empiric strategy to protect against infectious diseases was introduced even before the advent of hygiene and antimicrobials in the medical practice. Nevertheless, it was not until a few decades ago that we really started understanding the underlying mechanisms of protection triggered by vaccination. Vaccines were initially based on attenuated or inactivated organisms. Subunit vaccines were then introduced as more refined formulations, exhibiting improved safety profiles. However, purified antigens tend to be poorly immunogenic and often require the use of adjuvants to achieve adequate stimulation of the immune system. Vaccination strategies, such as mucosal administration, also require potent adjuvants to improve performance. In the 1990s, immunologists found that pathogens could be sensed as ‘danger signals’ by receptors recognizing conserved motifs. Although our knowledge is still limited, tremendous advances were made in the understanding of host defence mechanisms regulated by these evolutionary conserved receptors, and the molecular structures which are recognized by them. This opened a new era in adjuvant development. Some of the latest players arrived to this field are the cyclic di‐nucleotides, which are ubiquitous prokaryotic intracellular signalling molecules. This review is focused on their potential for the development of vaccines and immunotherapies.

Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants

“…CDNs are a relatively new class of immunomodulatory compounds with the potential to promote protective immunity through a unique pathway using the cytosolic danger sensor STING and its downstream transcription factors NF-κB and IRF-3 (6,63). The publication of crystal structures demonstrating the structural basis for CDN sensing through STING (64,65) and the identification of endogenous CDNs as signaling products produced by cyclic GMP-AMP synthase sensing of double-stranded DNA (9,10,66) have provided both a rationale and mechanistic guidance for the development of CDNs as adjuvants acting through type I IFNs and NF-κB activation in host cells.…”

MPYS/STING-Mediated TNF-α, Not Type I IFN, Is Essential for the Mucosal Adjuvant Activity of (3′–5′)-Cyclic-Di-Guanosine-Monophosphate In Vivo

“…Both DNA and cyclic dinucleotides have promising adjuvant activity (32). Previous studies (19, 21) showed that the adjuvant activity of DNA requires STING and IFN-I.…”

“…Cyclic dinucleotides are promising adjuvant candidates (32). In light of our current finding, we suggest that 2ʹ5ʹ−3ʹ5ʹ cGAMP, generated during DNA sensing, requires IFN-I for its adjuvant activity, whereas the 3ʹ5ʹ−3ʹ5ʹ cyclic dinucleotide, similar to CDG and CDA, uses a TNF-α–dependent mechanism to mediate its adjuvant activity.…”

Mucosal Adjuvants

“…Concomitantly, many substances that act as mucosal adjuvants have been described and investigated; some of these have remarkable immunomodulatory properties and great potential for use in human vaccines. The majority of these adjuvants use one of three mechanisms to initiate immune activation: (1) toxin-mediated immune stimulation initiated after binding to non-Tolllike receptors (non-TLRs), such as glycosphingolipids, on the surface of the host cell; the best representatives of this kind of adjuvant are cholera toxin and the heat-labile toxin produced by Escherichia coli (Lawson et al, 2010;Liang et al, 2009b;Clements et al, 1988;Freytag and Clements, 2005;Elson, 1989); (2) substances that are recognized by cells of the innate immune response as microbial components and are ligands for pattern-recognition receptors; examples of these are TLR agonists, such as lipopolysaccharide (LPS), flagellin, CpG DNA, dsRNA, imidazoquinolines, and peptidoglycans, each with unique and distinct receptors found in antigen-presenting cells (APCs), epithelial cells, and other cells that participate in innate microbial recognition (Abreu, 2010;Zeytun et al, 2007;Underhill and Ozinsky, 2002); and (3) naturally occurring immunomodulators such as cytokines, complement fragments, and messenger molecules (Dempsey et al, 1996;Toapanta and Ross, 2006;Taylor, 1995;Libanova et al, 2012;Bradney et al, 2002) (Figure 1). Particulate adjuvants such as microspheres, nano-or microparticles, and various polymers used to encapsulate antigens, have been used as carriers or adjuvants for mucosal vaccines, but will not be further discussed in this chapter.…”