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Orders Norzivirales and Timlovirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
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).
Mucosal vaccine strategies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Nils Lycke, Jan Holmgren, Harry B. Greenberg
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.
Non-Vaccine VLPs
Published in Paul Pumpens, 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).
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].
Development of CpG oligodeoxynucleotide TLR9 agonists in anti-cancer therapy
Published in Expert Review of Anticancer Therapy, 2021
Yizhen Jin, Yuxin Zhuang, Xiaowu Dong, Mei Liu
From 1988, when researchers discovered that the deoxyribonucleic acid fraction from mycobacterium could trigger the release of human interferon-α (IFN-α) of natural killer (NK) cells, to 1995, when CpG motifs in bacterial DNA was found to have to ability to directly activate B–cells [12], CpG oligodeoxynucleotide(ODN) have been regarded as a promising vaccine adjuvant as well as a immunotherapeutic for cancer, allergic and infectious diseases [13]. Notably, TLR9 agonists showed good efficacy in combination with immune checkpoint inhibitors (CPI) [14–19]. Clinical strategies aiming to transform ‘cold tumor’ to ‘hot tumor’ thereby highlight TLR9 as a promising target in anti-tumor immunotherapy. Up to now, the development of TLR9 agonists has gone through four generations. However, even though huge companies including Pfizer and Novartis have been plowing in the area of TLR9 agonists in immunotherapy for years, no drug has been approved so far. Therefore, this review focused mainly on the representatives of each generation of TLR9 agonists and the results of preclinical studies together with clinical trials and discussed the advantages and limitations in their application in immunotherapy.
Phagocytosis: Phenotypically Simple Yet a Mechanistically Complex Process
Published in International Reviews of Immunology, 2020
The activation of TLRs in microglia by TLR1/2 (Pam3CSK4), TLR4 (LPS) and TLR9 (CpG oligodeoxynucleotide) ligands enhances the PU and killing of the S. pneumoniae [241]. Furthermore, the microglia stimulation with different TLR ligands (Pam3CSK4, LPS and CpGODN) also increases the phagocytosis (PU and ICK) of E. coli DH5α and E. coli K1 strains [242]. The stimulation of different macrophages (Alveolar, peritoneal and bone marrow-derived macrophages) with TLR2, TLR3 and TLR4 ligands enhances the IgG-opsonized sheep RBC (IgG-sRBC) phagocytosis, but TLR9 ligands fail [243]. The leukotriene B4 (LTB4) production and the ERK1/ERK2 phosphorylation mediate this effect. The mechanism needs further investigation in the phagocytosis of bacterial pathogens. The TLR2 enrichment into the phagosome containing yeast occurs during phagocytosis, and a point mutation in the TLR2 abrogates the pro-inflammatory immune response to Gram-positive bacteria and yeast but not to the Gram-negative bacteria [159]. Thus, during phagocytosis, two classes of receptors called primary phagocytic receptors (MRs, SRs, FcγRs) and PRRs (TLRs that sample the contents of the vacuole and trigger an inflammatory immune response are required to clear the pathogen).