Modified polyriboinosinic-polyribocytidylic acid, an immunological adjuvant

Houston, William E.; Crabbs, C. L.; Stephen, Edward L.; Levy, Harold B.

doi:10.1128/iai.14.1.318-319.1976

Cited by 30 publications

(5 citation statements)

References 9 publications

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“…Fimaporfin was provided at 30 mg/ml in 3% polysorbate 80, 2.8% mannitol, 50 mM Tris, pH 8.5 (Amphinex formulation) and was kept light protected at 2–8°C. The adjuvant poly-ICLC (Hiltonol) is a synthetic double-stranded RNA complex of poly(IC) stabilized with poly-L-lysine polylysine and carboxymethylcellulose ( 19 ). Hiltonol 2 mg/ml was purchased from Oncovir (Washington DC, USA) and kept at 2–8°C (when aliquoted it was used within 14 days).…”

Section: Methodsmentioning

confidence: 99%

Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers

Otterhaug

Janetzki²,

Welters

et al. 2021

Front. Immunol.

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Background and AimsPhotochemical internalization (PCI) is a technology for inducing release of endocytosed antigens into the cell cytosol via a light-induced process. Preclinical experiments have shown that PCI improves MHC class I antigen presentation, resulting in strongly enhanced CD8+ T-cell responses to polypeptide antigens. In PCI vaccination a mixture of the photosensitizing compound fimaporfin, vaccine antigens, and an adjuvant is administered intradermally followed by illumination of the vaccination site. This work describes an open label, phase I study in healthy volunteers, to assess the safety, tolerability, and immune response to PCI vaccination in combination with the adjuvant poly-ICLC (Hiltonol) (ClinicalTrials.gov Identifier: NCT02947854).MethodsThe primary objective of the study was to assess the safety and local tolerance of PCI mediated vaccination, and to identify a safe fimaporfin dose for later clinical studies. A secondary objective was to analyze the immunological responses to the vaccination. Each subject received 3 doses of HPV16 E7 peptide antigens and two doses of Keyhole Limpet Hemocyanin (KLH) protein. A control group received Hiltonol and vaccine antigens only, whereas the PCI groups in addition received fimaporfin + light. Local and systemic adverse effects were assessed by standard criteria, and cellular and humoral immune responses were analyzed by ELISpot, flow cytometry, and ELISA assays.Results96 healthy volunteers were vaccinated with fimaporfin doses of 0.75–50 µg. Doses below 17.5 µg were safe and tolerable, higher doses exhibited local tolerability issues in some study subjects, mainly erythema, and pain during illumination. There were few, and only mild and expected systemic adverse events. The employment of PCI increased the number of subjects exhibiting a T-cell response to the HPV peptide vaccine about 10-fold over what was achieved with the antigen/Hiltonol combination without PCI. Moreover, the use of PCI seemed to result in a more consistent and multifunctional CD8+ T-cell response. An enhancement of the humoral immune response to KLH vaccination was also observed.ConclusionsUsing PCI in combination with Hiltonol for intradermal vaccination is safe at fimaporfin doses below 17.5 µg, and gives encouraging immune responses to peptide and protein based vaccination.

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Section: Methodsmentioning

confidence: 99%

Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers

Otterhaug

Janetzki²,

Welters

et al. 2021

Front. Immunol.

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“…Poly (ICLC) adjuvant activity has been shown when co-administered with retinoic acid [ 58 ], VEEV vaccine [ 59 , 60 ] and the antimalarial drug chloroquine [ 61 ]. Synergism of poly (ICLC) with various anti-HIV compounds including cytokines (rIFN-α A, rIFN-β Ser 17, and rIFN-γ), reverse transcriptase inhibitors (azidothymidine and phosphonoformate (Foscarnet)), mRNA capping inhibitors (ribavirin), lipophile (amphotericin B) and glucosidase inhibitor (castanospermine) was observed [ 62 ].…”

Section: Tlr3 Agonists: Dsrnamentioning

confidence: 99%

Broad-Spectrum Drugs Against Viral Agents

Christopher

Wong

2008

IJMS

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Development of antivirals has focused primarily on vaccines and on treatments for specific viral agents. Although effective, these approaches may be limited in situations where the etiologic agent is unknown or when the target virus has undergone mutation, recombination or reassortment. Augmentation of the innate immune response may be an effective alternative for disease amelioration. Nonspecific, broad-spectrum immune responses can be induced by double-stranded (ds)RNAs such as poly (ICLC), or oligonucleotides (ODNs) containing unmethylated deocycytidyl-deoxyguanosinyl (CpG) motifs. These may offer protection against various bacterial and viral pathogens regardless of their genetic makeup, zoonotic origin or drug resistance.

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“…It is not yet understood, however, how TLR7 and TLR8, whose endogenous ligands are single-stranded viral RNA (ssRNA), recognize and transduce signals upon engagement by small, nonpolymeric molecules such as the imidazoquinolines , and the oxoadenines. , We were not only desirous of examining the effect of variously configured, preorganized dimeric constructs of the imidazoquinolines on TLR7 and TLR8 in our continuing efforts to identify efficacious and safe vaccine adjuvants but also motivated in the hope that we may, by design or accident, discover small-molecule modulators of TLR3. It may be noted that although TLR3, like TLR7, is an attractive target for adjuvant design and development, − polyriboinosinic:polyribocytidylic acid, poly(I:C), is presently the only available synthetic TLR3 agonist . No small molecule agonists for TLR3 have been described to date; however, benzothiophene antagonists of TLR3 have been reported recently …”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor (TLR)-7 and -8 Modulatory Activities of Dimeric Imidazoquinolines

et al. 2012

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Toll-like receptors (TLRs) are pattern recognition receptors that recognize specific molecular patterns present in molecules that are broadly shared by pathogens, but are structurally distinct from host molecules. The TLR7-agonistic imidazoquinolines are of interest as vaccine adjuvants given their ability to induce pronounced Th1-skewed humoral responses. Minor modifications on the imidazoquinoline scaffold result in TLR7-antagonistic compounds which may be of value in addressing innate immune activation-driven immune exhaustion observed in HIV. We describe the syntheses and evaluation of TLR7 and TLR8 modulatory activities of dimeric constructs of imidazoquinoline linked at the C2, C4, C8, and N1-aryl positions. Dimers linked at the C4, C8 and N1-aryl positions were agonistic at TLR7; only the N1-aryl dimer with a 12-carbon linker was dual TLR7/8 agonistic. Dimers linked at C2 position showed antagonistic activities at TLR7 and TLR8; the C2 dimer with a propylene spacer was maximally antagonistic at both TLR7 and TLR8.

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Modified polyriboinosinic-polyribocytidylic acid, an immunological adjuvant

Cited by 30 publications

References 9 publications

Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers

Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers

Broad-Spectrum Drugs Against Viral Agents

Toll-Like Receptor (TLR)-7 and -8 Modulatory Activities of Dimeric Imidazoquinolines

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