ArticlePloS one2015
The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant.Cytokine · 2016Trial
- A dual-adjuvanted HA stem nanoparticle vaccine elicits a multifunctional antibody response that is associated with protection in newborn monkeys.Cell reports. Medicine · 2026Article
- Vaccination of newborn monkeys with an influenza HA stem nanoparticle adjuvanted with R848 and AddaVax results in broadened HA recognition and increased antibody secreting cells to HA stem following H1N1 challenge.Frontiers in immunology · 2026Article
- Integration of TLR7/8 agonists into lipid nanoparticles enhances antigen-specific immune responses to N1-methyl-Ψ-modified mRNA-LNP vaccines.Journal of biological engineering · 2025Article
- Antibody function predicts viral control in newborn monkeys immunised with an influenza virus HA stem nanoparticle.Nature communications · 2025Article
- Modulation of the Adjuvant Potential of Imidazoquinoline-Based TLR7/8 Agonists via Alum Adsorption.ACS medicinal chemistry letters · 2024Article
- Design and Synthesis of Polyphenolic Imidazo[4,5-ACS pharmacology & translational science · 2024Article
- From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation.Science advances · 2024Article
- An Analysis of Linker-Dependent Effects on the APC Activation and In Vivo Immunogenicity of an R848-Conjugated Influenza Vaccine.Vaccines · 2023Article
- A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future.Pharmaceutics · 2023Review
- Synthesis and immunopharmacological evaluation of novel TLR7 agonistic triazole tethered imidazoquinolines.RSC advances · 2023Article
- Site-Specific Multi-Functionalization of the Carrier Protein CRMChembiochem : a European journal of chemical biology · 2022Article
- Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination.Scientific reports · 2022Article
- Shaping Neonatal Immunization by Tuning the Delivery of Synergistic Adjuvants via Nanocarriers.ACS chemical biology · 2022Article
- Analysis of R848 as an Adjuvant to Improve Inactivated Influenza Vaccine Immunogenicity in Elderly Nonhuman Primates.Vaccines · 2022Article
- Molecular dynamics simulations reveal the selectivity mechanism of structurally similar agonists to TLR7 and TLR8.PloS one · 2022Article
- Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants.Advanced drug delivery reviews · 2021Review
- Structural evolution of toll-like receptor 7/8 agonists from imidazoquinolines to imidazoles.RSC medicinal chemistry · 2021Review
- Understanding Antibody Responses in Early Life: Baby Steps towards Developing an Effective Influenza Vaccine.Viruses · 2021Review
- Structural and functional understanding of the toll-like receptors.Protein science : a publication of the Protein Society · 2021Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundNewborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848).
methodsTLRA-induced NF-κB activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2.
resultsHybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-α, and IL-1β. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848.
conclusionsHybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.