Library Subscription: Guest
Begell Digital Portal Begell Digital Library eBooks Journals References & Proceedings Research Collections
Critical Reviews™ in Immunology
IF: 1.404 5-Year IF: 3.347 SJR: 0.706 SNIP: 0.55 CiteScore™: 2.19

ISSN Print: 1040-8401
ISSN Online: 2162-6472

Volume 40, 2020 Volume 39, 2019 Volume 38, 2018 Volume 37, 2017 Volume 36, 2016 Volume 35, 2015 Volume 34, 2014 Volume 33, 2013 Volume 32, 2012 Volume 31, 2011 Volume 30, 2010 Volume 29, 2009 Volume 28, 2008 Volume 27, 2007 Volume 26, 2006 Volume 25, 2005 Volume 24, 2004 Volume 23, 2003 Volume 22, 2002 Volume 21, 2001 Volume 20, 2000 Volume 19, 1999 Volume 18, 1998 Volume 17, 1997 Volume 16, 1996 Volume 15, 1995 Volume 14, 1994

Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.2019027183
pages 1-14

RNA-Based Adjuvants: Immunoenhancing Effect on Antiviral Vaccines and Regulatory Considerations

Annett Ziegler
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research (joint venture between the Hannover Medical School and Helmholtz Centre for Infection Research), 30625 Hannover, Germany
Thomas Hinz
Division Immunology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, 63225 Langen, Germany
Ulrich Kalinke
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research (joint venture between the Hannover Medical School and Helmholtz Centre for Infection Research), 30625 Hannover, Germany; Cluster of Excellence: Resolving Infection Susceptibility (RESIST), Hannover Medical School, 30625 Hannover, Germany


During the last decade, a wide variety of cellular RNA sensors and structural characteristics of their agonists have been identified. On the basis of this knowledge, RNA formulations were developed as innovative adjuvant candidates. In contrast to DNA, RNA does not have genotoxic potential and is rapidly degraded. In many aspects, RNA mimics viral infections and induces considerably strong immune responses. Additionally, RNA-based adjuvants can be designed so that distinct RNA sensors can be triggered according to requirements of individual vaccines. Furthermore, RNA can be synthesized in vitro in a cell-free system, and recent developments in formulation technology have led to reduced RNA degradation within the body. These features qualify RNA as a promising adjuvant candidate. Here, we discuss latest developments in the field of RNA-based adjuvants and highlight differences between human and mouse nucleic acid sensors, which constitute a challenge in the development of RNA-based adjuvants. Finally, we discuss how RNA-based adjuvants are currently handled with regard to regulatory requirements.


  1. Caskey M, Lefebvre F, Filali-Mouhim A, Cameron MJ, Goulet JP, Haddad EK, Breton G, Trumpfheller C, Pollak S, Shimeliovich I, Duque-Alarcon A, Pan L, Nelkenbaum A, Salazar AM, Schlesinger SJ, Steinman RM, Sekaly RP. Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J Exp Med. 2011 Nov 21;208(12):2357-66.

  2. Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, Akira S, Ahmed R, Pulendran B. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med. 2006 Feb 20;203(2):413-24.

  3. Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, Swanson JA, Muller M, Blander JM. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature. 2011 Jun 17. 16;474(7351):385-9.

  4. Schlake T, Thess A, Fotin-Mleczek M, Kallen KJ. Developing mRNA-vaccine technologies. RNA Biol. 2012 Nov;9(11):1319-30.

  5. Fotin-Mleczek M, Duchardt KM, Lorenz C, Pfeiffer R, Ojkic-Zrna S, Probst J, Kallen KJ. Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J Immunother. 2011 Jan;34(1):1-15.

  6. Kallen KJ, Heidenreich R, Schnee M, Petsch B, Schlake T, Thess A, Baumhof P, Scheel B, Koch SD, Fotin-Mleczek M. A novel, disruptive vaccination technology: Self-adjuvanted RNActive vaccines. Hum Vaccin Immunother. 2013 0ct;9(10):2263-76.

  7. Desmet CJ, Ishii KJ. Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat Rev Immunol. 2012 Jul;12(7):479-91.

  8. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kB by Toll-like receptor 3. Nature. 2001 Oct 18;413(6857):732-8.

  9. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004 Mar 5;303(5663):1529-31.

  10. Oldenburg M, Kruger A, Ferstl R, Kaufmann A, Nees G, Sigmund A, Bathke B, Lauterbach H, Suter M, Dreher S, Koedel U, Akira S, Kawai T, Buer J, Wagner H, Bauer S, Hochrein H, Kirschning CJ. TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science. 2012 Aug 31;337(6098):1111-5.

  11. Li XD, Chen ZJ. Sequence specific detection of bacterial 23S ribosomal RNA by TLR13. Elife. 2012 Oct 30;1:e00102.

  12. Hidmark A, von Saint Paul A, Dalpke AH. Cutting edge: TLR13 is a receptor for bacterial RNA. J Immunol. 2012 Sep 15;189(6):2717-21.

  13. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S. Human TLR7 or TLR8 independently confers responsiveness to the antiviral compound R-848. Nat Immunol. 2002 Jun;3(6):499.

  14. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002 Feb;3(2):196-200.

  15. Demaria O, Pagni PP, Traub S, de Gassart A, Branzk N, Murphy AJ, Valenzuela DM, Yancopoulos GD, Flavell RA, Alexopoulou L. TLR8 deficiency leads to autoimmunity in mice. J Clin Invest. 2010 Oct;120(10):3651-62.

  16. Martinez J, Huang X, Yang Y. Toll-like receptor 8-mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA. Proc Natl Acad Sci USA. 2010 Apr 6;107(14):6442-7.

  17. Awais M, Wang K, Lin X, Qian W, Zhang N, Wang C, Wang K, Zhao L, Fu ZF, Cui M. TLR7 deficiency leads to TLR8 compensative regulation of immune response against JEV in mice. Front Immunol. 2017;8:160.

  18. Edwards AD, Diebold SS, Slack EM, Tomizawa H, Hemmi H, Kaisho T, Akira S, Reis e Sousa C. Toll-like receptor expression in murine DC subsets: Lack of TLR7 expression by CD8a+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol. 2003 Apr;33(4):827-33.

  19. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ. Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens. J Exp Med. 2001 Sep 17;194(6):863-9.

  20. Barr TA, Brown S, Ryan G, Zhao J, Gray D. TLR-mediated stimulation of APC: Distinct cytokine responses of B cells and dendritic cells. Eur J Immunol. 2007 Nov;37(11):3040-53.

  21. Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G. Quantitative expression of Toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002 May 1;168(9):4531-7.

  22. Lindstedt M, Lundberg K, Borrebaeck CA. Gene family clustering identifies functionally associated subsets of human in vivo blood and tonsillar dendritic cells. J Immunol. 2005 Oct 15;175(8):4839-46.

  23. Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, Chen CJ, Dunbar PR, Wadley RB, Jeet V, Vulink AJ, Hart DN, Radford KJ. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010 Jun 7;207(6):1247-60.

  24. Yamazaki C, Miyamoto R, Hoshino K, Fukuda Y, Sasaki I, Saito M, Ishiguchi H, Yano T, Sugiyama T, Hemmi H, Tanaka T, Hamada E, Hirashima T, Amakawa R, Fukuhara S, Nomura S, Ito T, Kaisho T. Conservation of a 37. chemokine system, XCR1 and its ligand, XCL1, between human and mice. Biochem Biophys Res Commun. 2010 Jul 9;397(4):756-61.

  25. Brinkmann MM, Spooner E, Hoebe K, Beutler B, Ploegh HL, Kim YM. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol. 2007 Apr 23;177(2):265-75.

  26. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, Homey B, Barrat FJ, Zal T, Gilliet M. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009 Aug 31;206(9):1983-94.

  27. Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006 Nov;6(11): 823-35.

  28. Hipp MM, Shepherd D, Booth S, Waithe D, Reis e Sousa C, Cerundolo V. The processed amino-terminal fragment of human TLR7 acts as a chaperone to direct human TLR7 into endosomes. J Immunol. 2015 Jun 1;194(11):5417-25.

  29. Kanno A, Tanimura N, Ishizaki M, Ohko K, Motoi Y, Onji M, Fukui R, Shimozato T, Yamamoto K, Shibata T, Sano S, Sugahara-Tobinai A, Takai T, Ohto U, Shimizu T, Saitoh S, Miyake K. Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases. Nat 41. Commun. 2015 Feb 4;6:6119.

  30. Bertheloot D, Naumovski AL, Langhoff P, Horvath GL, Jin T, Xiao TS, Garbi N, Agrawal S, Kolbeck R, Latz E. RAGE Enhances TLR responses through binding and internalization of RNA. J Immunol. 2016 Nov 15;197(10):4118-26.

  31. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, Cao W, Wang YH, Su B, Nestle FO, Zal T, Mellman I, Schroder JM, Liu YJ, Gilliet M. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007 Oct 4;449(7162):564-9.

  32. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010 Mar 19;140(6):805-20.

  33. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, TakaokaA, Taya C, Taniguchi T. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature. 2005 Apr 21;434(7036):1035-40.

  34. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N, Taniguchi T. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005 Apr 7;434(7034):772-7.

  35. Barchet W, Cella M, Odermatt B, Asselin-Paturel C, Colonna M, Kalinke U. Virus-induced interferon a production by a dendritic cell subset in the absence of feedback signaling in vivo. J Exp Med. 2002 Feb 18;195(4):507-16.

  36. Hemont C, Neel A, Heslan M, Braudeau C, Josien R. Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. J Leukoc Biol. 2013 Apr;93(4):599-609.

  37. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M, Jr., Akira S, Yonehara S, Kato A, Fujita T. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 2005 Sep 1;175(5):2851-8.

  38. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G. 5'-Triphosphate RNA is the ligand for RIG-I. Science. 2006 Nov 10;314(5801):994-7.

  39. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med. 2008 Jul 7;205(7):1601-10.

  40. Schlee M, Roth A, Hornung V, Hagmann CA, Wimmenauer V, Barchet W, Coch C, Janke M, Mihailovic A, Wardle G, Juranek S, Kato H, Kawai T, Poeck H, Fitzgerald KA, Takeuchi O, Akira S, Tuschl T, Latz E, Ludwig J, Hartmann G. Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity. 2009 Jul 17;31(1):25-34.

  41. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006 May 4;441(7089):101-5.

  42. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, Reis e Sousa C. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science. 2006 Nov 10;314(5801):997-1001.

  43. Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks BG, Schoenemeyer A, Yamamoto M, Akira S, Fitzgerald KA. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol. 2005 Oct 15;175(8):5260-8.

  44. Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O. LGP2 is a positive regulator of RIG-I- and MDA5- mediated antiviral responses. Proc Natl Acad Sci USA.

  45. Parisien JP, Lenoir JJ, Mandhana R, Rodriguez KR, Qian K, Bruns AM, Horvath CM. RNA sensor LGP2 inhibits TRAF ubiquitin ligase to negatively regulate innate immune signaling. EMBO Rep. 2018 Jun;19(6):e45176.

  46. van der Veen AG, Maillard PV, Schmidt JM, Lee SA, Deddouche-Grass S, Borg A, Kjaer S, Snijders AP, Reis ESC. The RIG-I-like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells. EMBO J. 2018 Feb 15;37(4):e97479.

  47. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S. IPS-1, an adaptor triggering RIG-I- and MDA5-mediated type I interferon induction. Nat Immunol. 2005 0ct;6(10):981-8.

  48. Meylan E, Curran J, Hofmann K, Moradpour D, Binder 61. M, Bartenschlager R, Tschopp J. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005 Oct 20;437(7062):1167-72.

  49. Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell RA, Diamond MS, Colonna M. Essential role of MDA-5 in type I IFN responses to polyriboinosinic: polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci USA. 2006 May 30;103(22):8459-64.

  50. Takahasi K, Yoneyama M, Nishihori T, Hirai R, Kumeta H, Narita R, Gale M, Jr., Inagaki F, Fujita T. Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol Cell. 2008 Feb 64. 29;29(4):428-40.

  51. Onomoto K, Onoguchi K, Takahasi K, Fujita T. Type I interferon production induced by RIG-I-like receptors. J Interferon Cytokine Res. 2010 Dec;30(12):875-81.

  52. Oshiumi H, Sakai K, Matsumoto M, Seya T. DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-P-inducing potential. Eur J Immunol. 2010 Apr;40(4):940-8.

  53. Zhang Z, Yuan B, Lu N, Facchinetti V, Liu YJ. DHX9 pairs with IPS-1 to sense double-stranded RNA in myeloid dendritic cells. J Immunol. 2011 Nov 1;187(9):4501-8.

  54. Zhang Z, Kim T, Bao M, Facchinetti V, Jung SY, Ghaffari AA, Qin J, Cheng G, Liu YJ. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity. 2011 Jun 24;34(6):866-78.

  55. Mitoma H, Hanabuchi S, Kim T, Bao M, Zhang Z, Sugimoto N, Liu YJ. The DHX33 RNA helicase senses cytosolic RNA and activates the NLRP3 inflammasome. Immunity. 2013 Jul 25;39(1):123-35.

  56. Feng GS, Chong K, Kumar A, Williams BR. Identification of double-stranded RNA-binding domains in the interferon-induced double-stranded RNA-activated p68 kinase. Proc Natl Acad Sci USA. 1992 Jun 15;89(12):5447-51.

  57. Pichlmair A, Lassnig C, Eberle CA, Gorna MW, Baumann CL, Burkard TR, Burckstummer T, Stefanovic A, Krieger S, Bennett KL, Rulicke T, Weber F, Colinge J, Muller M, Superti-Furga G. IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA. Nat Immunol. 2011 Jun 5;12(7):624-30.

  58. Coffman RL, Sher A, Seder RA. Vaccine adjuvants: Putting innate immunity to work. Immunity. 2010 Oct 29;33(4):492-503.

  59. McKee AS, Munks MW, Marrack P. How do adjuvants work? Important considerations for new generation adjuvants. Immunity. 2007 Nov;27(5):687-90.

  60. Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, Lekeux P, Coban C, Akira S, Ishii KJ, Bureau F, Desmet CJ. DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med. 2011 Aug;17(8):996-1002.

  61. Longhi MP, Trumpfheller C, Idoyaga J, Caskey M, Matos I, Kluger C, Salazar AM, Colonna M, Steinman RM. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med. 2009 Jul 6;206(7):1589-602.

  62. Levine AS, Levy HB. Phase I-II trials of poly IC stabilized with poly-L-ly sine. Cancer Treat Rep. 1978 Nov;62(11):1907-12.

  63. Robinson RA, DeVita VT, Levy HB, Baron S, Hubbard SP, Levine AS. A phase I-II trial of multiple-dose polyriboinosic-polyribocytidylic acid in patients with leukemia or solid tumors. J Natl Cancer Inst. 1976 Sep;57(3):599-602.

  64. Ichinohe T, Kawaguchi A, Tamura S, Takahashi H, Sawa H, Ninomiya A, Imai M, Itamura S, Odagiri T, Tashiro M, Chiba J, Sata T, Kurata T, Hasegawa H. Intranasal immunization with H5N1 vaccine plus Poly I:Poly C12U, a Toll-like receptor agonist, protects mice against homologous and heterologous virus challenge. Microbes Infect. 2007 Sep;9(11):1333-40.

  65. Thompson KA, Strayer DR, Salvato PD, Thompson CE, Klimas N, Molavi A, Hamill AK, Zheng Z, Ventura D, Carter WA. Results of a double-blind placebo-controlled study of the double-stranded RNA drug polyI:polyC12U in the treatment of HIV infection. Eur J Clin Microbiol Infect Dis. 1996 Jul;15(7):580-7.

  66. Gowen BB, Wong MH, Jung KH, Sanders AB, Mitchell WM, Alexopoulou L, Flavell RA, Sidwell RW. TLR3 is essential for the induction of protective immunity against Punta Toro virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not Poly(I:C): Differential recognition of synthetic dsRNA molecules. J Immunol. 2007 Apr 15;178(8):5200-8.

  67. Stahl-Hennig C, Eisenblatter M, Jasny E, Rzehak T, Tenner-Racz K, Trumpfheller C, Salazar AM, Uberla K, Nieto K, Kleinschmidt J, Schulte R, Gissmann L, Muller M, Sacher A, Racz P, Steinman RM, Uguccioni M, Ignatius R. Synthetic double-stranded RNAs are adjuvants for the induction of T helper 1 and humoral immune responses to human papillomavirus in rhesus macaques. PLoS Pathog. 2009 Apr;5(4):e1000373.

  68. Rehwinkel J, Tan CP, Goubau D, Schulz O, Pichlmair A, Bier K, Robb N, Vreede F, Barclay W, Fodor E, Reis e Sousa C. RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell. 2010 Feb 5;140(3):397-408.

  69. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M, Jr. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature. 2008 Jul 24;454(7203):523-7.

  70. Rodriguez-Pulido M, Martin-Acebes MA, Escribano. Romero E, Blazquez AB, Sobrino F, Borrego B, Saiz M, Saiz JC. Protection against West Nile virus infection in mice after inoculation with type I interferon-inducing RNA transcripts. PLoS One. 2012;7(11):e49494.

  71. Rodriguez-Pulido M, Borrego B, Sobrino F, Saiz M. RNA structural domains in noncoding regions of the foot-and- mouth disease virus genome trigger innate immunity in porcine cells and mice. J Virol. 2011 Jul;85(13):6492-501.

  72. Baum A, Sachidanandam R, Garcia-Sastre A. Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing. Proc Natl Acad Sci USA. 2010 Sep 14;107(37):16303-8.

  73. Martinez-Gil L, Goff PH, Hai R, Garcia-Sastre A, Shaw ML, Palese P. A Sendai virus-derived RNA agonist of RIG-I as a virus vaccine adjuvant. J Virol. 2013 Feb;87(3):1290-300.

  74. Mercado-Lopez X, Cotter CR, Kim WK, Sun Y, Munoz L, Tapia K, Lopez CB. Highly immunostimulatory RNA derived from a Sendai virus defective viral genome. Vaccine. 2013 Nov 19;31(48):5713-21.

  75. Fisher DG, Coppock GM, Lopez CB. Virus-derived immunostimulatory RNA induces type I IFN-dependent antibodies and T-cell responses during vaccination. Vaccine. 2018 Jun 27;36(28):4039-45.

  76. Beljanski V, Chiang C, Kirchenbaum GA, Olagnier D, Bloom CE, Wong T, Haddad EK, Trautmann L, Ross TM, Hiscott J. Enhanced influenza virus-like particle vaccination with a structurally optimized RIG-I agonist as adjuvant. J Virol. 2015 Oct;89(20):10612-24.

  77. Chiang C, Beljanski V, Yin K, Olagnier D, Ben Yebdri F, Steel C, Goulet ML, DeFilippis VR, Streblow DN, Haddad EK, Trautmann L, Ross T, Lin R, Hiscott J. Sequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists. J Virol. 2015 Aug;89(15):8011-25.

  78. Oberson A, Spagnuolo L, Puddinu V, Barchet W, Rittner K, Bourquin C. NAB2 is a novel immune stimulator of MDA-5 that promotes a strong type I interferon response. Oncotarget. 2018 Jan 19;9(5):5641-51.

  79. Matsumoto M, Tatematsu M, Nishikawa F, Azuma M, Ishii N, Morii-Sakai A, Shime H, Seya T. Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo. Nat Commun. 2015;6:6280.

  80. Carignan D, Herblot S, Laliberte-Gagne ME, Bolduc M, Duval M, Savard P, Leclerc D. Activation of innate immunity in primary human cells using a plant virus derived nanoparticle TLR7/8 agonist. Nanomedicine. 2018 Oct;14(7):2317-27.

  81. Therien A, Bedard M, Carignan D, Rioux G, Gauthier-Landry L, Laliberte-Gagne ME, Bolduc M, Savard P, Leclerc D. A versatile papaya mosaic virus (PapMV) vaccine platform based on sortase-mediated antigen coupling. J Nanobiotechnol. 2017 Jul 18;15(1):54.

  82. Rajagopal D, Paturel C, Morel Y, Uematsu S, Akira S, Diebold SS. Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists. Blood. 2010 Mar 11;115(10):1949-57.

  83. Madera RF, Wang JP, Libraty DH. The combination of early and rapid type I IFN, IL-1a, and IL-ip production are essential mediators of RNA-like adjuvant driven CD4+ Th1 responses. PLoS One. 2011;6(12):e29412.

  84. Ziegler A, Soldner C, Lienenklaus S, Spanier J, Trittel S, Riese P, Kramps T, Weiss S, Heidenreich R, Jasny E, Guzman CA, Kallen KJ, Fotin-Mleczek M, Kalinke U. A new RNA-based adjuvant enhances virus-specific vaccine responses by locally triggering TLR- and RLH-dependent effects. J Immunol. 2017 Feb 15;198(4):1595-605.

  85. Heidenreich R, Jasny E, Kowalczyk A, Lutz J, Probst J, Baumhof P, Scheel B, Voss S, Kallen KJ, Fotin-Mleczek M. A novel RNA-based adjuvant combines strong immunostimulatory capacities with a favorable safety profile. Int J Cancer. 2015 Jul 15;137(2):372-84.

  86. Circelli L, Petrizzo A, Tagliamonte M, Heidenreich R, Tornesello ML, Buonaguro FM, Buonaguro L. Immunological effects of a novel RNA-based adjuvant in liver cancer patients. Cancer Immunol Immunother. 2017 Jan;66(1):103-12.

  87. Bookstaver ML, Tsai SJ, Bromberg JS, Jewell CM. Improving vaccine and immunotherapy design using biomaterials. Trends Immunol. 2018 Feb;39(2):135-50.

  88. Negishi H, Yanai H, Nakajima A, Koshiba R, Atarashi K, Matsuda A, Matsuki K, Miki S, Doi T, Aderem A, Nishio J, Smale ST, Honda K, Taniguchi T. Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses. Nat Immunol. 2012 May 20;13(7): 659-66.

  89. Negishi H, Matsuki K, Endo N, Sarashina H, Miki S, Matsuda A, Fukazawa K, Taguchi-Atarashi N, Ikushima H, Yanai H, Nishio J, Honda K, Fujioka Y, Ohba Y, Noda T, Taniguchi S, Nishida E, Zhang Y, Chi H, Flavell RA, Taniguchi T. Beneficial innate signaling interference for antibacterial responses by a Toll-like receptor-mediated enhancement of the MKP-IRF3 axis. Proc Natl Acad Sci USA. 2013 Dec 3;110(49):19884-9.

  90. Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol. 2011 Sep 4;12(10):959-65.

  91. Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, Hannesschlager N, Schlee M, Rothenfusser S, Barchet W, Kato H, Akira S, Inoue S, Endres S, Peschel C, Hartmann G, Hornung V, Ruland J. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin ip production. Nat Immunol. 2010 Jan;11(1):63-9.

  92. Szabo A, Magyarics Z, Pazmandi K, Gopcsa L, Rajnavolgyi E, Bacsi A. TLR ligands upregulate RIG-I expression in human plasmacytoid dendritic cells in a type I IFN-independent manner. Immunol Cell Biol. 2014 Sep;92(8):671-8.

  93. Hochheiser K, Klein M, Gottschalk C, Hoss F, Scheu S, Coch C, Hartmann G, Kurts C. Cutting edge: The RIG-I ligand 3pRNA potently improves CTL cross-priming and facilitates antiviral vaccination. J Immunol. 2016 Mar 15;196(6):2439-43.

  94. Bourquin C, Schmidt L, Lanz AL, Storch B, Wurzenberger C, Anz D, Sandholzer N, Mocikat R, Berger M, Poeck H, Hartmann G, Hornung V, Endres S. Immunostimulatory RNA oligonucleotides induce an effective antitumoral NK cell response through the TLR7. J Immunol. 2009 Nov 15;183(10):6078-86.

  95. Berger M, Hsieh CY, Bakele M, Marcos V, Rieber 100 N, Kormann M, Mays L, Hofer L, Neth O, Vitkov L, Krautgartner WD, von Schweinitz D, Kappler R, Hector A, Weber A, Hartl D. Neutrophils express distinct RNA receptors in a non-canonical way. J Biol Chem. 2012 Jun 101 1;287(23):19409-17.

  96. Rodriguez-Rodrigues N, Castillo LA, Landoni VI, Martire-Greco D, Milillo MA, Barrionuevo P, Fernandez GC. Prokaryotic RNA associated to bacterial viability induces polymorphonuclear neutrophil activation. Front Cell Infect Microbiol. 2017;7:306.

  97. Calabro S, Tortoli M, Baudner BC, Pacitto A, Cortese M, O'Hagan DT, De Gregorio E, Seubert A, Wack A. Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine. 2011 Feb 17;29(9):1812-23.

  98. Lundberg AM, Drexler SK, Monaco C, Williams LM, Sacre SM, Feldmann M, Foxwell BM. Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: A phenomenon absent from murine cell systems. Blood. 2007 Nov 1;110(9):3245-52.

  99. Ugolini M, Gerhard J, Burkert S, Jensen KJ, Georg P, Ebner F, Volkers SM, Thada S, Dietert K, Bauer L, Schafer A, Helbig ET, Opitz B, Kurth F, Sur S, Dittrich N, Gaddam S, Conrad ML, Benn CS, Blohm U, Gruber AD, Hutloff A, Hartmann S, Boekschoten MV, Muller M, Jungersen G, Schumann RR, Suttorp N, Sander LE. Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses. Nat Immunol. 2018 Apr;19(4):386-96.

  100. Barbet G, Sander LE, Geswell M, Leonardi I, Cerutti A, Iliev I, Blander JM. Sensing microbial viability through bacterial RNA augments T follicular helper cell and antibody responses. Immunity. 2018 Mar 20;48(3):584-98.

  101. Hinz T, Kallen K, Britten CM, Flamion B, Granzer U, Hoos A, Huber C, Khleif S, Kreiter S, Rammensee HG, Sahin U, Singh-Jasuja H, Tureci O, Kalinke U. The European regulatory environment of RNA-based vaccines. Methods Mol Biol. 2017;1499:203-22.

Articles with similar content:

HITS-CLIP and PAR-CLIP Advance Viral MiRNA Targetome Analysis
Critical Reviews™ in Eukaryotic Gene Expression, Vol.24, 2014, issue 2
Irina Haecker, Rolf Renne
Transcutaneous Immunization: An Emerging Route of Immunization and Potent Immunostimulation Strategy
Critical Reviews™ in Therapeutic Drug Carrier Systems, Vol.18, 2001, issue 5
Scott A. Hammond, Gregory M. Glenn, Mimi Guebre-Xabier, Jianmei Yu
Pharmaceutical Cocrystals: A Novel Approach for Oral Bioavailability Enhancement of Drugs
Critical Reviews™ in Therapeutic Drug Carrier Systems, Vol.29, 2012, issue 3
Renu Chadha, Poonam Arora, Swati Bhandari, Anupam Saini
Inhibition of Hepatitis B Virus with the Help of CRISPR/Cas9 Technology
Critical Reviews™ in Eukaryotic Gene Expression, Vol.30, 2020, issue 3
Akhtar Rasul, Muhammad Imran Qadir, Muhammad Shahid Iqbal, Muhammad Sajid Hamid Akash, Bilal Ahmed, Sadaf Noor
Strategies to enhance NK cell function for the treatment of tumors and infections
Critical Reviews™ in Immunology, Vol.38, 2018, issue 2
Taku Kambayashi, Jacquelyn Freund-Brown, Leilani Chirino