Emulsion-based Vaccine Adjuvants

Reed, Steven G.; Fox, Christopher B.; Carter, Darrick

doi:10.2217/9781780840604

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…This IDRI emulsion formulation is similar to formulations already approved in Europe for influenza vaccines, MF59 and AS03, but in addition contains TLR4 ligand GLA. Emulsions like these effectively and safely induce immune responses to influenza antigens, including enabling dose sparing [31][32][33] . The mice were immunized with either ToxAll with the adjuvant GLA-SE, Empty-SAPN with GLA-SE, GLA-SE only, or PBS.…”

Section: Resultsmentioning

confidence: 99%

Engineering and characterization of a novel Self Assembling Protein for Toxoplasma peptide vaccine in HLA-A11:01, HLA-A02:01 and HLA-B*07:02 transgenic mice

Bissati

Zhou

Paulillo³

et al. 2020

Sci Rep

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Fighting smart diseases requires smart vaccines. Novel ways to present protective immunogenic peptide epitopes to human immune systems are needed. Herein, we focus on Self Assembling Protein Nanoparticles (SAPNs) as scaffolds/platforms for vaccine delivery that produce strong immune responses against Toxoplasma gondii in HLA supermotif, transgenic mice. Herein, we present a useful platform to present peptides that elicit CD4+, CD8+ T and B cell immune responses in a core architecture, formed by flagellin, administered in combination with TLR4 ligand-emulsion (GLA-SE) adjuvant. We demonstrate protection of HLA-A*11:01, HLA-A*02:01, and HLA-B*07:02 mice against toxoplasmosis by (i) this novel chimeric polypeptide, containing epitopes that elicit CD8+ T cells, CD4+ T helper cells, and IgG2b antibodies, and (ii) adjuvant activation of innate immune TLR4 and TLR5 pathways. HLA-A*11:01, HLA-A*02:01, and HLA-B*07:02q11 transgenic mouse splenocytes with peptides demonstrated predicted genetic restrictions. This creates a new paradigm-shifting vaccine approach to prevent toxoplasmosis, extendable to other diseases.

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Section: Resultsmentioning

confidence: 99%

Engineering and characterization of a novel Self Assembling Protein for Toxoplasma peptide vaccine in HLA-A11:01, HLA-A02:01 and HLA-B*07:02 transgenic mice

Bissati

Zhou

Paulillo³

et al. 2020

Sci Rep

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“…Synthetic MPLA (Avanti Lipids, United States) is a complex molecule, with a disaccharide core and linear and branched fatty acid chains with a stereogenic center at C-3, whose synthesis is long (>25 steps) with elevated production costs (the present cost of MPLA is ~230 USD/mg in the American market). Furthermore, MPLA synthesis (699800P Avanti MPLA (PHAD ® ); Reed and Carter, 2014) is based on a massive use of "red" or environmentally undesirable solvents such as Pyridine or DMF (Alfonsi et al, 2008;Byrne et al, 2016;Joshi and Adhikari, 2019).…”

Section: Open Access Edited Bymentioning

confidence: 99%

Cleaner synthesis of preclinically validated vaccine adjuvants

Romerio,

Peri

2023

Front. Chem.

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We developed synthetic glycophospholipids based on a glucosamine core (FP compounds) with potent and selective activity in stimulating Toll-Like Receptor 4 (TLR4) as agonists. These compounds have activity and toxicity profiles similar to the clinically approved adjuvant monophosphoryl lipid A (MPLA), included in several vaccine formulations, and are now in the preclinical phase of development as vaccine adjuvants in collaboration with Croda International PLC. FP compound synthesis is shorter and less expensive than MPLA preparation but presents challenges due to the use of toxic solvents and hazardous intermediates. In this paper we describe the optimization of FP compound synthesis. The use of regio- and chemoselective reactions allowed us to reduce the number of synthesis steps and improve process scalability, overall yield, safety, and Process Mass Intensity (PMI), thus paving the way to the industrial scale-up of the process.

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“…The Glucopyranosyl Lipid Adjuvant (GLA, Figure 4 ) has been developed by Avanti Polar Lipids Inc. as a fully synthetic MPLA analog with TLR4 agonistic activity (tradename: phosphorylated hexa-acyl disaccharide PHAD®) ( 55 , 56 ). Being fully synthetic, the main advantage of this compound is its chemical homogeneity, which improves activity and safety with respect to MPLA, a semi-synthetic molecule.…”

Section: Glycolipid-based Tlr4 Modulatorsmentioning

confidence: 99%

Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

Romerio

Peri

2020

Front. Immunol.

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Toll-Like Receptor 4 (TLR4) is one of the receptors of innate immunity. It is activated by Pathogen- and Damage-Associated Molecular Patterns (PAMPs and DAMPs) and triggers pro-inflammatory responses that belong to the repertoire of innate immune responses, consequently protecting against infectious challenges and boosting adaptive immunity. Mild TLR4 stimulation by non-toxic molecules resembling its natural agonist (lipid A) provided efficient vaccine adjuvants. The non-toxic TLR4 agonist monophosphoryl lipid A (MPLA) has been approved for clinical use. This suggests the development of other TLR4 agonists as adjuvants or drugs for cancer immunotherapy. TLR4 excessive activation by a Gram-negative bacteria lipopolysaccharide (LPS) leads to sepsis, while TLR4 stimulation by DAMPs is a common mechanism in several inflammatory and autoimmune diseases. TLR4 inhibition by small molecules and antibodies could therefore provide access to innovative therapeutics targeting sepsis as well as acute and chronic inflammations. The potential use of TLR4 antagonists as anti-inflammatory drugs with unique selectivity and a new mechanism of action compared to corticosteroids or other non-steroid anti-inflammatory drugs fueled the search for compounds of natural or synthetic origin able to block or inhibit TLR4 activation and signaling. The wide spectrum of clinical settings to which TLR4 inhibitors can be applied include autoimmune diseases (rheumatoid arthritis, inflammatory bowel diseases), vascular inflammation, neuroinflammations, and neurodegenerative diseases. The last advances (from 2017) in TLR4 activation or inhibition by small molecules (molecular weight <2 kDa) are reviewed here. Studies on pre-clinical validation of new chemical entities (drug hits) on cellular or animal models as well as new clinical studies on previously developed TLR4 modulators are reported. Innovative TLR4 modulators discovered by computer-assisted drug design and an artificial intelligence approach are described. Some “old” TLR4 agonists or antagonists such as MPLA or Eritoran are under study for repositioning in different pharmacological contexts. The mechanism of action of the molecules and the level of TLR4 involvement in their biological activity are critically discussed.

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Emulsion-based Vaccine Adjuvants

Cited by 6 publications

References 11 publications

Engineering and characterization of a novel Self Assembling Protein for Toxoplasma peptide vaccine in HLA-A11:01, HLA-A02:01 and HLA-B*07:02 transgenic mice

Engineering and characterization of a novel Self Assembling Protein for Toxoplasma peptide vaccine in HLA-A11:01, HLA-A02:01 and HLA-B*07:02 transgenic mice

Cleaner synthesis of preclinically validated vaccine adjuvants

Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

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Emulsion-based Vaccine Adjuvants

Cited by 6 publications

References 11 publications

Engineering and characterization of a novel Self Assembling Protein for Toxoplasma peptide vaccine in HLA-A*11:01, HLA-A*02:01 and HLA-B*07:02 transgenic mice

Engineering and characterization of a novel Self Assembling Protein for Toxoplasma peptide vaccine in HLA-A*11:01, HLA-A*02:01 and HLA-B*07:02 transgenic mice

Cleaner synthesis of preclinically validated vaccine adjuvants

Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

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Product

Resources

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Engineering and characterization of a novel Self Assembling Protein for Toxoplasma peptide vaccine in HLA-A11:01, HLA-A02:01 and HLA-B*07:02 transgenic mice

Engineering and characterization of a novel Self Assembling Protein for Toxoplasma peptide vaccine in HLA-A11:01, HLA-A02:01 and HLA-B*07:02 transgenic mice