Orders Norzivirales and Timlovirales
Paul Pumpens, Peter Pushko, Philippe Le Mercier in Virus-Like Particles, 2022
The CpG oligonucleotides were studied successfully together with the model VLPs by Bachmann’s team, first with the HBc VLPs (Storni et al. 2002, 2003; Schwarz K et al. 2003; Storni and Bachmann 2003). The CpG packaging into both HBc and Qβ VLPs provided with the previously mentioned LCMV gp33 epitope followed (Bachmann et al. 2004b; Storni et al. 2004). Storni et al. (2004) and showed that the packaging of CpGs into the HBc or Qβ VLPs was not only simple but could reduce the two major problems of the CpG usage, namely their unfavorable pharmacokinetics and systemic side effects, including splenomegaly. The vaccination with the CpG-loaded VLPs was able to induce high frequencies of peptide-specific CD8+ T cells. It protected from infection with recombinant vaccinia viruses and eradicated established solid fibrosarcoma tumors. It was concluded therefore for the first time that packaging CpGs into the Qβ VLPs improved both their immunogenicity and pharmacodynamics (Storni et al. 2004). This study paved the long way for the development of the CpG containing VLP vaccine candidates, especially in the allergy vaccines elaborated by Bachmann’s team, as described earlier in the Vaccines paragraph. The Qβ VLP vaccines carrying packaged CpG were reviewed in the global context of the CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies (Hanagata 2017; Bachmann et al. 2020; Jensen-Jarolim et al. 2020).
Non-Vaccine VLPs
Paul Pumpens in Single-Stranded RNA Phages, 2020
The packaging of the Qβ VLPs with immunostimulatory CpG sequences led not only to the development of potential allergy vaccines, as described in the Chemical coupling section of Chapter 22, but also strongly contributed to the general understanding of the mechanics of oligodeoxynucleotide-induced stimulation (Bachmann et al. 2004b, 2005a; Storni et al. 2004; Schwarz et al. 2005; Agnellini et al. 2008; Bessa et al. 2008; Senti et al. 2009; Keller et al. 2010a, 2010b; Hou et al. 2011; Klimek et al. 2011, 2013a; Link et al. 2012; Beeh et al. 2013; Casale et al. 2015), as narrated in the Basic immunology section of Chapter 22. The Qβ VLP vaccines carrying packaged CpG were reviewed in the global context of the CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies (Hanagata 2017). Furthermore, the Qβ VLP vaccines were ranked on a par with the total E. coli–derived VLPs in vaccine development (Huang et al. 2017).
Mucosal vaccine strategies
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
In principle, adjuvants may exploit three types of modulating effects on the innate immune system that will impact the adaptive immune response and promote improved immunogenicity (Figure 30.3). The first type of effect occurs with adjuvants that contain TLR- or NOD-like receptor (NLR) agonists. These are dominated by the former, such as MPL, a chemically modified derivative of LPS and a TLR4 agonist, flagellin (TLR-5 agonist), or CpG-oligodeoxynucleotide (TLR9 agonist), which have been found to be the most effective. However, relative to the bacterial holotoxins CT and heat-labile enterotoxin, they are poor mucosal adjuvants, especially for mucosal SIgA responses (see Figure 30.3). The holotoxins, on the other hand, do not use TLRs or NLRs to activate the innate immune system. A third category of mucosal adjuvants are functionally less distinct. These are oil-in-water emulsions, immune-stimulating complexes containing cytokines, such as IL-1, or mucoadhesive substances, such as chitosan. This third category exploits many different mechanisms of action; eventually it may be shown that some act through TLR binding, but in most cases, their function is poorly known, and hence, we cannot explain how they work in any greater detail when part of a mucosal vaccine.
The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study
Published in Pediatric Hematology and Oncology, 2019
Rebecca Ronsley, Amina Kariminia, Bernard Ng, Sara Mostafavi, Gregor Reid, Peter Subrt, Nobuko Hijiya, Kirk R. Schultz
Toll-like receptor (TLR) is a family of ten related molecules that recognize structurally conserved molecules derived from microbes and play a key role in innate immunity. Synthetic single-stranded oligonucleotides containing unmethylated cytosine and guanine (CpG) motifs (CpG-oligodeoxynucleotide [CpG-ODN]) function as an immune stimulant and binds to TLR9 on plasmacytoid dendritic cells and B-cells, and results in production of various cytokines including IL6, IL10, gamma interferon, IL12, IL18, TNF alpha and interferon alpha as well as increase immunoglobulin production and increases in MHC-II expression and the expression of co-stimulatory molecules. It may be possible to harness this immunomodulatory action as an anti cancer therapy.13 Previously, it was demonstrated that CpG-ODN (GNKG168) stimulated up-regulation of co-stimulatory molecule expression and cytokine production in vitro by pediatric ALL cells, resulting in enhanced allogeneic Th1 T cell responses against ALL.14 The ability of the GNKG168 to induce immune activity against primary human ALL cells in vivo using NOD-SCID mice has also been reported.15 More recently, pre-B ALL cell model mice were treated with GNKG168 starting 7 days after injection with ALL cells mimicking minimal residual disease (MRD) state and achieved T-cell dependent remission for over 6 months.14
How does an RNA selfie work? EV-associated RNA in innate immunity as self or danger
Published in Journal of Extracellular Vesicles, 2020
Yu Xiao, Tom Driedonks, Kenneth W. Witwer, Qian Wang, Hang Yin
Altering EV trafficking could be another route to changing the perception of carried nucleic acids. Supporting this possibility, EVs secreted from CpG oligodeoxynucleotide (ODN)-activated macrophages transported ODN into naïve macrophages, stimulating TLR9 and enhancing the release of chemokine tumour necrosis factor–α (TNF-α) [22]. EV-associated ODN was resistant to protease, and protease and nuclease treatment of ODN-EV did not affect the release of TNF-α, suggesting that ODN may be enclosed within EVs. Furthermore, EVs from ODN-activated macrophages contained increased Cdc42 levels, which increased the uptake of EVs in recipient cells (Figure 1). Knockdown of Cdc42 in recipient cells could be restored by EV-associated Cdc42, resulting in increased EV uptake. This suggests that EV uptake in unmodified recipient cells was a result of EV-associated Cdc42, although it is possible that autocrine TNF-α signalling might also contribute. Although it is not yet clear if similar modulation might occur for RNA cargo, these results may point to an activation-induced feedback mechanism to enhance EVmediated entry of PAMPs/DAMPs into recipient cells. These findings not only shed light on the activation of innate immunity but also suggest a previously unidentified regulation strategy for these important biological pathways [22].
Polysaccharide-based hydrogels for drug delivery and wound management: a review
Published in Expert Opinion on Drug Delivery, 2022
Dhruv Sanjanwala, Vaishali Londhe, Rashmi Trivedi, Smita Bonde, Sujata Sawarkar, Vinita Kale, Vandana Patravale
He et al. developed a hydrogel composed of aldehyde mannan and N,O-carboxymethyl chitosan. The hydrogel played a dual role as an adjuvant as well as antigen carrier. Using a model antigen (ovalbumin), the authors showed that the hydrogel promoted dendritic cell uptake of the antigen and produced 12.5 times more antigen-specific IgG antibodies than the routinely used aluminum-based adjuvant [297]. In another study, a group of researchers prepared a vaccine against COVID-19 using injectable hydrogel NPs composed of dodecyl-modified HPMC (HPMC-C12) and PEG-b-poly(lactic acid). The receptor-binding domain (RBD) of the spike protein of the SARS-CoV-2 virus was used as an antigen. The RBD has low immunogenicity, hence to improve its immunogenicity, alum and CpG oligodeoxynucleotide were used as adjuvants. The gel could be easily injected using a 21-gauge needle, forming a solid depot in the subcutaneous region. This ensured a sustained release of RBD from the depot producing a more potent immune response. The vaccine formulation was able to produce large quantities of anti-RBD antibodies that were also able to neutralize the alpha (B.1.1.7, first identified in the United Kingdom) and beta (B.1.351, first identified in South Africa) variants of the SARS-CoV-2 [298]. The same research group also developed and tested another injectable HPMC-C12 hydrogel-based vaccine against COVID-19 using RBD and cGAMP (a secondary messenger of the innate immune system) as an adjuvant (unpublished) [299].
Related Knowledge Centers
- Cytosine
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- Methylation
- Phosphodiester Bond
- Guanine
- Thiophosphate
- Sequence Motif
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