BBIQ, a pure TLR7 agonist, is an effective influenza vaccine adjuvant

References

• Petrovsky N. Comparative safety of vaccine adjuvants: a summary of current evidence and future needs. Drug Saf. 2015;38:1059–74. doi:10.1007/s40264-015-0350-4.
   PubMed Web of Science ®Google Scholar
• Warshakoon HJ, Hood JD, Kimbrell MR, Malladi S, Wu WY, Shukla NM, Agnihotri G, Sil D, David SA. Potential adjuvantic properties of innate immune stimuli. Hum Vaccin. 2009;5:381–94. doi:10.4161/hv.5.6.8175.
   PubMed Web of Science ®Google Scholar
• Petrovsky N, Aguilar JC. Vaccine adjuvants: current state and future trends. Immunol Cell Biol. 2004;82:488–96. doi:10.1111/imcb.2004.82.issue-5.
   PubMed Web of Science ®Google Scholar
• Dowling DJ. Recent advances in the discovery and delivery of TLR7/8 agonists as vaccine adjuvants. Immuno Horizons. 2018;2:185–97. doi:10.4049/immunohorizons.1700063.
   Google Scholar
• Awate S, Babiuk LA, Mutwiri G. Mechanisms of action of adjuvants. Front Immunol. 2013;4:114. doi:10.3389/fimmu.2013.00114.
   PubMed Web of Science ®Google Scholar
• To EE, Erlich J, Liong F, Luong R, Liong S, Bozinovski S, Seow HJ, O’Leary JJ, Brooks DA, Vlahos R, et al. Intranasal and epicutaneous administration of Toll-Like Receptor 7 (TLR7) agonists provides protection against influenza A virus-induced morbidity in mice. Sci Rep. 2019;9:2366. doi:10.1038/s41598-019-38864-5.
   PubMed Web of Science ®Google Scholar
• Shukla NM, Malladi SS, Mutz CA, Balakrishna R, David SA. Structure-activity relationships in human Toll-Like Receptor 7-active imidazoquinoline analogues. J Med Chem 2010;53:4450–65. doi:10.1021/jm100358c.
   PubMed Web of Science ®Google Scholar
• Beesu M, Caruso G, Salyer ACD, Khetani KK, Sil D, Weerasinghe M, Tanji H, Ohto U, Shimizu T, David SA. Structure-based design of human TLR8-specific agonists with augmented potency and adjuvanticity. J Med Chem 2015;58:7833−7849). doi:10.1021/acs.jmedchem.5b01087.
   PubMed Web of Science ®Google Scholar
• Beesu M, Salyer ACD, Trautman KL, Hill JK, David SA. Human Toll-Like Receptor (TLR) 8‑specific agonistic activity in substituted pyrimidine-2,4-diamines. J Med Chem 2016;59:8082−8093).
   Web of Science ®Google Scholar
• Beesu M, Malladi SS, Fox LM, Jones CD, Dixit A, David SA. Human Toll-Like Receptor 8‑selective agonistic activities in 1‑alkyl‑1H‑benzimidazol-2-amines. J Med Chem 2014;57:7325−7341). doi:10.1021/jm500701q.
   PubMed Web of Science ®Google Scholar
• Beesu M, Caruso G, Salyer ACD, Shukla NM, Khetani KK, Smith LJ, Fox LM, Tanji H, Ohto U, Shimizu T, et al. Identification of a human Toll-Like Receptor (TLR) 8-specific agonist and a functional pan-TLR inhibitor in 2-aminoimidazoles. J Med Chem 2016;59:3311−3330.
   PubMed Web of Science ®Google Scholar
• Gupta S, Vayuvegula B, Gollapudi S. Substituted guanine ribonucleosides as B cell activators. Clin Immunol Immunopathol. 1991;61:s21–s27. doi:10.1016/S0090-1229(05)80034-0.
   PubMedGoogle Scholar
• Pope BL, Chourmouzis E, Sigindere J, MacIntyre JP, Capetola RJ, Lau CY. In vivo activation of natural killer cells and priming of IL-2 responsive cytolytic cells by loxoribine (7-allyl-8-oxoguanosine). Cell Immunol. 1993;147:302–12. doi:10.1006/cimm.1993.1071.
   PubMed Web of Science ®Google Scholar
• Pope BL, Chourmouzis E, Victorino L, MacIntyre JP, Capetola RJ, Lau CY. Loxoribine (7-allyl-8-oxoguanosine) activates natural killer cells and primes cytolytic precursor cells for activation by IL-2. J Immunol. 1993;151:3007–17.
   PubMed Web of Science ®Google Scholar
• Hoeven NV, Fox CB, Granger B, Evers T, Joshi SW, Nana GI, Evans SC, Lin S, Liang H, Liang L, et al. A formulated TLR7/8 agonist is a flexible, highly potent and effective adjuvant for pandemic influenza vaccines. Sci Rep 2017;7:46426. doi:10.1038/srep46426.
   PubMed Web of Science ®Google Scholar
• Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X, Tomai MA, Alkan SS, Vasilakos JP. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 2005;174:1259–68. doi:10.4049/jimmunol.174.3.1259.
   PubMed Web of Science ®Google Scholar
• Levy O, Suter E,E, Miller R,L, Wessels M,R. Unique efficacy of Toll-Like Receptor 8 agonists in activating human neonatal antigen-presenting cells. Blood. 2006;108:1284–90. doi:10.1182/blood-2005-12-4821.
   PubMed Web of Science ®Google Scholar
• Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Keiper WC, Qiu X, Tomai MA, Alkan SS, Vasilakos JP. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 2005;174:1259−1268. doi:10.4049/jimmunol.174.3.1259.
   PubMed Web of Science ®Google Scholar
• Beesu M, Salyer ACD, Brush MJH, Trautman KL, Hill JK, David SA. Identification of high-potency Human TLR8 and dual TLR7/TLR8 agonists in pyrimidine-2,4-diamines. J Med Chem 2017;60:2084−2098. doi:10.1021/acs.jmedchem.6b01860.
   PubMed Web of Science ®Google Scholar
• Salyer ACD, David SA. Transcriptomal signatures of vaccine adjuvants and accessory immunostimulation of sentinel cells by Toll-Like Receptor 2/6 agonists. Hum Vaccin Immunother 2018;14:1686–1696.
   PubMed Web of Science ®Google Scholar
• Salyer ACD, Caruso G, Khetani KK, Fox LM, Malladi SS, David SA. Identification of adjuvantic activity of amphotericin B in a Novel, multiplexed, Poly- TLR/NLR high-throughput screen. PLoS One. 2016;11(2):e0149848. doi:10.1371/journal.pone.0149848.
   PubMed Web of Science ®Google Scholar
• Ganapathi L, Haren SV, Dowling DJ, Bergelson I, Shukla NM, Malladi SS, Balakrishna R, Tanji H, Ohto U, Shimizu T, et al. The imidazoquinoline Toll-Like Receptor-7/8 agonist hybrid-2 potently induces cytokine production by human newborn and adult leukocytes. PLoS One. 2015;10(8):e0134640. doi:10.1371/journal.pone.0134640.
   PubMed Web of Science ®Google Scholar
• Shi C, Xiong Z, Chittepu P, Aldrich CC, Ohlfest JR, Ferguson DM. Discovery of imidazoquinolines with Toll-Like Receptor 7/8 independent cytokine induction. ACS Med Chem Lett 2012;3:501−504. doi:10.1021/ml300079e.
   PubMed Web of Science ®Google Scholar
• Yoo E, Salunke DB, Sil D, Guo X, Salyer ACD, Hermanson AR, Kumar M, Malladi SS, Balakrishna R, Thompson,W H, et al. Determinants of activity at Human Toll-like Receptors 7 and 8: quantitative Structure−Activity Relationship (QSAR) of diverse heterocyclic scaffolds. J Med Chem 2014;57:7955−7970. doi:10.1021/jm500744f.
   PubMed Web of Science ®Google Scholar
• Kokatla HP, Sil D, Malladi SS, Balakrishna R, Hermanson AR, Fox LM, Wang X, Dixit A, David SA. Exquisite selectivity for human Toll-Like Receptor 8 in substituted Furo[2,3‑c]quinolines. J Med Chem 2013;56:6871−6885. doi:10.1021/jm400694d.
   PubMed Web of Science ®Google Scholar
• Saroa R, Kaushik D, Bagai U, Kaur S, Salunke DB. Efficacy of TLR7 agonistic imidazoquinoline as immunochemotherapeutic agent against P. Berghei ANKA infected rodent host. Bioorg Med Chem Letts. 2019;29:1099–105. doi:10.1016/j.bmcl.2019.02.029.
   PubMed Web of Science ®Google Scholar
• Shukla NM, Kimbrell MR, Malladi SS, David SS. Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline. Bioorg Med Chem Lett 2009;19:2211–14. doi:10.1016/j.bmcl.2009.02.100.
   PubMed Web of Science ®Google Scholar
• Angelos SA, Meyers JA. The isolation and identification of precursors and reaction products in the clandestine manufacture of methaqualone and mecloqualone. J Forensic Sci. 1985;30:1022–47. doi:10.1520/JFS11044J.
   PubMed Web of Science ®Google Scholar
• Schiaffo CE, Shi C, Xiong Z, Olin M, Ohlfest JR, Aldrich CC, Ferguson DM. Structure−activity relationship analysis of imidazoquinolines with Toll-Like Receptors 7 and 8 selectivity and enhanced cytokine induction. J Med Chem 2014;57:339–47. doi:10.1021/jm4004957.
   PubMed Web of Science ®Google Scholar
• Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605–12.
   PubMed Web of Science ®Google Scholar
• Spoel DVD, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC, Fast GROMACS. Flexible, and Free. J Comput Chem 2005;26:1701–18. doi:10.1002/jcc.20291.
   PubMed Web of Science ®Google Scholar
• Korb O, Stützle T, Exner TE. Empirical scoring functions for advanced Protein−Ligand docking with PLANTS. J Chem Inf Model 2009;49:84–96. doi:10.1021/ci800298z.
   PubMed Web of Science ®Google Scholar
• Kumari R, Kumar R, Lynn A. g_mmpbsa—a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 2014;54:1951–62. doi:10.1021/ci500020m.
   PubMed Web of Science ®Google Scholar
• Honda-Okubo Y, Barnard D, Ong CH, Peng BH, Tseng CT, Petrovsky N. SARS-CoV vaccines formulated with delta inulin adjuvants provide enhanced virus protection while ameliorating lung eosinophilic immunopathology. J Virol. 2015 Mar;89(6):2995–3007.
   Google Scholar
• Hung IF, Zhang AJ, To KK, Chan JF, Li P, Wong TL, Zhang R, Chan T-C, Chan BCY, Wai HH, et al. Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b/3 trial. Lancet Infect Dis. 2016;16:209–18. doi:10.1016/S1473-3099(15)00354-0.
   PubMed Web of Science ®Google Scholar
• Thomsen LL, Topley P, Daly MG, Brett SJ, Tite JP. Imiquimod and resiquimod in a mouse model: adjuvants for DNA vaccination by particle-mediated immunotherapeutic delivery. Vaccine. 2004;22:1799–809. doi:10.1016/j.vaccine.2003.09.052.
   PubMed Web of Science ®Google Scholar
• Smorlesi A, Papalini F, Orlando F, Donnini A, Re F, Provinciali PM. Imiquimod and S-27609 as adjuvants of DNA vaccination in a transgenic murine model of HER2/neu-positive mammary carcinoma. Gene Ther. 2005;12:1324–32. doi:10.1038/sj.gt.3302559.
   PubMed Web of Science ®Google Scholar
• Zhang AJ, Li C, To KK, Zhu HS, Lee AC, Li CG, Chan JFW, Hung IFN, Yuen K-Y. Toll-Like Receptor 7 agonist imiquimod in combination with influenza vaccine expedites and augments humoral immune responses against influenza A(H1N1)pdm09 virus infection in BALB/c mice. Clin Vaccine Immunol. 2014;21:570–79. doi:10.1128/CVI.00816-13.
   PubMed Web of Science ®Google Scholar
• Bagnoli F, Fontana MR, Soldaini E, Mishra RP, Fiaschi L, Cartocci E, Nardi-Dei V, Ruggiero P, Nosari S, De Falco MG, et al. Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus. Proc Natl Acad Sci U S A. 2015;112:3680–85. doi:10.1073/pnas.1424924112.
   PubMed Web of Science ®Google Scholar
• Yoo E, Salyer ACD, Brush MJH, Li Y, Trautman KL, Shukla NM, De Beuckelaer A, Lienenklaus S, Deswarte K, Lambrecht BN, et al. Hyaluronic Acid Conjugates of TLR7/8 Agonists for Targeted Delivery to Secondary Lymphoid Tissue. Bioconjug Chem. 2018;29:2741–54. doi:10.1021/acs.bioconjchem.8b00386.
   PubMed Web of Science ®Google Scholar
• Lynn GM, Laga R, Darrah PA, Ishizuka AS, Balaci AJ, Dulcey AE, Pechar M, Pola R, Gerner MY, Yamamoto A, et al. In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity. Nat Biotechnol. 2015;33:1201–10. doi:10.1038/nbt.3371.
   PubMed Web of Science ®Google Scholar