A new RNA-based adjuvant enhances virus-specific vaccine responses by locally triggering TLR- and RLH-dependent effects

Journal of Immunology

Volumn 198, Issue 4, 2017, Pages 1595-1605

  Ziegler, Annett ^a   Soldner, Claudia ^a   Lienenklaus, Stefan ^a,b,c   Spanier, Julia ^a   Trittel, Stephanie ^b   Riese, Peggy ^b   Kramps, Thomas ^d,e   Weiss, Siegfried ^b   Heidenreich, Regina ^d   Jasny, Edith ^d   Guzmán, Carlos A ^b   Kallen, Karl Josef ^d,f   Fotin Mleczek, Mariola ^d   Kalinke, Ulrich ^a  

^a INSTITUTE OF INFECTION IMMUNOLOGY   (Germany)

^b HELMHOLTZ CENTRE FOR INFECTION RESEARCH   (Germany)

^c HANNOVER MEDICAL SCHOOL   (Germany)

^d CureVac GmbH   (Germany)

^e BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^f ETheRNA Immunotherapies NV   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

GUANINE NUCLEOTIDE BINDING PROTEIN; IMMUNOGLOBULIN G; IMMUNOGLOBULIN G2; IMMUNOGLOBULIN G2B; IMMUNOGLOBULIN G2C; INFLUENZA VACCINE; INTERFERON; MYELOID DIFFERENTIATION FACTOR 88; ODN 2216; RESIQUIMOD; RETINOIC ACID INDUCIBLE PROTEIN I; RNA; TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR AGONIST; UNCLASSIFIED DRUG; DDX58 PROTEIN, MOUSE; G PROTEIN, VESICULAR STOMATITIS VIRUS; IMMUNOLOGICAL ADJUVANT; MEMBRANE PROTEIN; MYD88 PROTEIN, MOUSE; SUBUNIT VACCINE; TLR7 PROTEIN, MOUSE; UNTRANSLATED RNA; VIRUS ANTIBODY; VIRUS ENVELOPE PROTEIN; VIRUS LIKE PARTICLE VACCINE;

ADJUVANT THERAPY; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL ACTIVATION; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RESPONSE; DENDRITIC CELL; EMBRYO; HUMAN; HUMAN CELL; IMMUNE RESPONSE; IMMUNOSTIMULATION; INFLUENZA; MOUSE; NONHUMAN; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; UPREGULATION; VESICULOVIRUS; VIRUS PARTICLE; ANIMAL; BAGG ALBINO MOUSE; BLOOD; DEFICIENCY; IMMUNOLOGY; METABOLISM; TH1 CELL; VACCINATION;

ADJUVANTS, IMMUNOLOGIC; ANIMALS; ANTIBODIES, VIRAL; DEAD BOX PROTEIN 58; IMMUNOGLOBULIN G; INFLUENZA VACCINES; MEMBRANE GLYCOPROTEINS; MICE; MICE, INBRED BALB C; MYELOID DIFFERENTIATION FACTOR 88; RNA, UNTRANSLATED; TH1 CELLS; TOLL-LIKE RECEPTOR 7; VACCINATION; VACCINES, SUBUNIT; VACCINES, VIRUS-LIKE PARTICLE; VIRAL ENVELOPE PROTEINS;

EID: 85014587588     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1601129     Document Type: Article

References (66)

1. Halperin, S. A., S. Dobson, S. McNeil, J. M. Langley, B. Smith, R. McCall-Sani, D. Levitt, G. V. Nest, D. Gennevois, and J. J. Eiden. 2006. Comparison of the safety and immunogenicity of hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide and a licensed hepatitis B vaccine in healthy young adults. Vaccine 24: 20-26.
2. Marrack, P., A. S. McKee, and M. W. Munks. 2009. Towards an understanding of the adjuvant action of aluminium. Nat. Rev. Immunol. 9: 287-293.
3. Kool, M., K. Fierens, and B. N. Lambrecht. 2012. Alum adjuvant: some of the tricks of the oldest adjuvant. J. Med. Microbiol. 61: 927-934.
4. Grun, J. L., and P. H. Maurer. 1989. Different T helper cell subsets elicited in mice utilizing two different adjuvant vehicles: the role of endogenous interleukin 1 in proliferative responses. Cell. Immunol. 121: 134-145.
5. Brewer, J. M., M. Conacher, A. Satoskar, H. Bluethmann, and J. Alexander. 1996. In interleukin-4-deficient mice, alum not only generates T helper 1 responses equivalent to Freund's complete adjuvant, but continues to induce T helper 2 cytokine production. Eur. J. Immunol. 26: 2062-2066.
6. Iwasaki, A., and R. Medzhitov. 2015. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16: 343-353.
7. McKeage, K., and B. Romanowski. 2011. AS04-adjuvanted human papillomavirus (HPV) types 16 and 18 vaccine (Cervarix-): a review of its use in the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic HPV types. Drugs 71: 465-488.
8. Giannini, S. L., E. Hanon, P. Moris, M. Van Mechelen, S. Morel, F. Dessy, M. A. Fourneau, B. Colau, J. Suzich, G. Losonksy, et al. 2006. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine 24: 5937-5949.
9. Napolitani, G., A. Rinaldi, F. Bertoni, F. Sallusto, and A. Lanzavecchia. 2005. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat. Immunol. 6: 769-776.
10. Zhu, Q., C. Egelston, A. Vivekanandhan, S. Uematsu, S. Akira, D. M. Klinman, I. M. Belyakov, and J. A. Berzofsky. 2008. Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc. Natl. Acad. Sci. USA 105: 16260-16265.
11. Querec, T., S. Bennouna, S. Alkan, Y. Laouar, K. Gorden, R. Flavell, S. Akira, R. Ahmed, and B. Pulendran. 2006. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J. Exp. Med. 203: 413-424.
12. Desmet, C. J., and K. J. Ishii. 2012. Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat. Rev. Immunol. 12: 479-491.
13. Sander, L. E., M. J.Davis,M.V. Boekschoten, D.Amsen, C. C. Dascher, B. Ryffel, J. A. Swanson, M. Muller, and J. M. Blander. 2011. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474: 385-389.
14. Diebold, S. S., T. Kaisho, H. Hemmi, S. Akira, and C. Reis e Sousa. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303: 1529-1531.
15. Alexopoulou, L., A. C. Holt, R. Medzhitov, and R. A. Flavell. 2001. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 732-738.
16. Schlee, M., E. Hartmann, C. Coch, V. Wimmenauer, M. Janke, W. Barchet, and G. Hartmann. 2009. Approaching the RNA ligand for RIG-I? Immunol. Rev. 227: 66-74.
17. Gitlin, L., W. Barchet, S. Gilfillan, M. Cella, B. Beutler, R. A. Flavell, M. S. Diamond, and M. Colonna. 2006. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA 103: 8459-8464.
18. Levine, A. S., and H. B. Levy. 1978. Phase I-II trials of poly IC stabilized with poly-L-lysine. Cancer Treat. Rep. 62: 1907-1912.
19. Hornung, V., J. Ellegast, S. Kim, K. Brzózka, A. Jung, H. Kato, H. Poeck, S. Akira, K. K. Conzelmann, M. Schlee, et al. 2006. 59-Triphosphate RNA is the ligand for RIG-I. Science 314: 994-997.
20. Matsumoto, M., M. Tatematsu, F. Nishikawa, M. Azuma, N. Ishii, A. Morii-Sakai, H. Shime, and T. Seya. 2015. Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo. Nat. Commun. 6: 6280.
21. Rajagopal, D., C. Paturel, Y. Morel, S. Uematsu, S. Akira, and S. S. Diebold. 2010. Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists. Blood 115: 1949-1957.
22. Kastenmuller, K., U. Wille-Reece, R. W. Lindsay, L. R. Trager, P. A. Darrah, B. J. Flynn, M. R. Becker, M. C. Udey, B. E. Clausen, B. Z. Igyarto, et al. 2011. Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets. J. Clin. Invest. 121: 1782-1796.
23. Madera, R. F., J. P. Wang, and D. H. Libraty. 2011. The combination of early and rapid type I IFN, IL-1a, and IL-1b production are essential mediators of RNAlike adjuvant driven CD4+ Th1 responses. PLoS One 6: e29412.
24. Scheel, B., R. Teufel, J. Probst, J. P. Carralot, J. Geginat, M. Radsak, D. Jarrossay, H. Wagner, G. Jung, H. G. Rammensee, et al. 2005. Toll-like receptor-dependent activation of several human blood cell types by protaminecondensed mRNA. Eur. J. Immunol. 35: 1557-1566.
25. Fotin-Mleczek, M., K. M. Duchardt, C. Lorenz, R. Pfeiffer, S. Ojkić-Zrna, J. Probst, and K. J. Kallen. 2011. Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J. Immunother. 34: 1-15.
26. Kallen, K. J., R. Heidenreich, M. Schnee, B. Petsch, T. Schlake, A. Thess, P. Baumhof, B. Scheel, S. D. Koch, and M. Fotin-Mleczek. 2013. A novel, disruptive vaccination technology: self-adjuvanted RNActive(-) vaccines. Hum. Vaccin. Immunother. 9: 2263-2276.
27. Kramps, T., S. Voss, J. Probst, and I. Hoerr. 2009. Nucleic acids comprising formula (NuGIXmGnNv)a and derivatives thereof as an immunostimulating agents/adjuvants. Available at: http://www.freepatentsonline.com/WO2009095226.html. Accessed: December 24, 2016.
28. Baumhof, P., K.-J. Kallen, T. Kramps, and S. Voss. 2012. Complexation of nucleic acids with disulfide-crosslinked cationic components for transfection and immunostimulation. Available at: http://www.freepatentsonline.com/WO2012013326.html. Accessed: December 24, 2016.
29. Muller, U., U. Steinhoff, L. F. Reis, S. Hemmi, J. Pavlovic, R. M. Zinkernagel, and M. Aguet. 1994. Functional role of type I and type II interferons in antiviral defense. Science 264: 1918-1921.
30. Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsutsui, M. Sakagami, K. Nakanishi, and S. Akira. 1998. Targeted disruption of the MyD88 gene results in loss of IL-1-and IL-18-mediated function. Immunity 9: 143-150.
31. Hoebe, K., X. Du, P. Georgel, E. Janssen, K. Tabeta, S. O. Kim, J. Goode, P. Lin, N. Mann, S. Mudd, et al. 2003. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424: 743-748.
32. Waibler, Z., M. Anzaghe, H. Ludwig, S. Akira, S. Weiss, G. Sutter, and U. Kalinke. 2007. Modified vaccinia virus Ankara induces Toll-like receptorindependent type I interferon responses. J. Virol. 81: 12102-12110.
33. Michallet, M. C., E. Meylan, M. A. Ermolaeva, J. Vazquez, M. Rebsamen, J. Curran, H. Poeck, M. Bscheider, G. Hartmann, M. König, et al. 2008. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28: 651-661.
34. Hemmi, H., T. Kaisho, O. Takeuchi, S. Sato, H. Sanjo, K. Hoshino, T. Horiuchi, H. Tomizawa, K. Takeda, and S. Akira. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3: 196-200.
35. Gu, H., Y. R. Zou, and K. Rajewsky. 1993. Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell 73: 1155-1164.
36. Erlandsson, L., R. Blumenthal, M. L. Eloranta, H. Engel, G. Alm, S. Weiss, and T. Leanderson. 1998. Interferon-beta is required for interferon-alpha production in mouse fibroblasts. Curr. Biol. 8: 223-226.
37. Lienenklaus, S., M. Cornitescu, N. Zietara, M. ?yszkiewicz, N. Gekara, J. Jab?ónska, F. Edenhofer, K. Rajewsky, D. Bruder, M. Hafner, et al. 2009. Novel reporter mouse reveals constitutive and inflammatory expression of IFN-beta in vivo. J. Immunol. 183: 3229-3236.
38. Soneoka, Y., P. M. Cannon, E. E. Ramsdale, J. C. Griffiths, G. Romano, S. M. Kingsman, and A. J. Kingsman. 1995. A transient three-plasmid expression system for the production of high titer retroviral vectors. Nucleic Acids Res. 23: 628-633.
39. Naldini, L., U. Blömer, P. Gallay, D. Ory, R. Mulligan, F. H. Gage, I. M. Verma, and D. Trono. 1996. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272: 263-267.
40. Bach, P., E. Kamphuis, B. Odermatt, G. Sutter, C. J. Buchholz, and U. Kalinke. 2007. Vesicular stomatitis virus glycoprotein displaying retrovirus-like particles induce a type I IFN receptor-dependent switch to neutralizing IgG antibodies. J. Immunol. 178: 5839-5847.
41. Heidenreich, R., E. Jasny, A. Kowalczyk, J. Lutz, J. Probst, P. Baumhof, B. Scheel, S. Voss, K. J. Kallen, and M. Fotin-Mleczek. 2015. A novel RNAbased adjuvant combines strong immunostimulatory capacities with a favorable safety profile. Int. J. Cancer 137: 372-384.
42. Bachmann, M. F., U. Kalinke, A. Althage, G. Freer, C. Burkhart, H. Roost, M. Aguet, H. Hengartner, and R. M. Zinkernagel. 1997. The role of antibody concentration and avidity in antiviral protection. Science 276: 2024-2027.
43. World Health Organization. 2011. Manual for the Laboratory Diagnosis and Virological Surveillance of Influenza. World Health Organization, Geneva, Switzerland.
44. Kamphuis, E., T. Junt, Z. Waibler, R. Forster, and U. Kalinke. 2006. Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia. Blood 108: 3253-3261.
45. Mosmann, T. R., and R. L. Coffman. 1989. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7: 145-173.
46. Yoneyama, M., M. Kikuchi, T. Natsukawa, N. Shinobu, T. Imaizumi, M. Miyagishi, K. Taira, S. Akira, and T. Fujita. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5: 730-737.
47. Sun, Q., L. Sun, H. H. Liu, X. Chen, R. B. Seth, J. Forman, and Z. J. Chen. 2006. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 24: 633-642.
48. Coffman, R. L., A. Sher, and R. A. Seder. 2010. Vaccine adjuvants: putting innate immunity to work. Immunity 33: 492-503.
49. Kovacs, D., P. Kovacs, N. Eszlari, X. Gonda, and G. Juhasz. 2016. Psychological side effects of immune therapies: symptoms and pathomechanism. Curr. Opin. Pharmacol. 29: 97-103.
50. Pestka, S. 2007. The interferons: 50 years after their discovery, there is much more to learn. J. Biol. Chem. 282: 20047-20051.
51. Dantzer, R. 2009. Cytokine, sickness behavior, and depression. Immunol. Allergy Clin. North Am. 29: 247-264.
52. Christian, L. M., K. Porter, E. Karlsson, and S. Schultz-Cherry. 2015. Proinflammatory cytokine responses correspond with subjective side effects after influenza virus vaccination. Vaccine 33: 3360-3366.
53. Caskey, M., F. Lefebvre, A. Filali-Mouhim, M. J. Cameron, J. P. Goulet, E. K. Haddad, G. Breton, C. Trumpfheller, S. Pollak, I. Shimeliovich, et al. 2011. Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J. Exp. Med. 208: 2357-2366.
54. Kato, H., O. Takeuchi, S. Sato, M. Yoneyama, M. Yamamoto, K. Matsui, S. Uematsu, A. Jung, T. Kawai, K. J. Ishii, et al. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441: 101-105.
55. Saito, T., D. M. Owen, F. Jiang, J. Marcotrigiano, and M. Gale, Jr. 2008. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454: 523-527.
56. Kato, H., K. Takahasi, and T. Fujita. 2011. RIG-I-like receptors: cytoplasmic sensors for non-self RNA. Immunol. Rev. 243: 91-98.
57. Kato, H., O. Takeuchi, E. Mikamo-Satoh, R. Hirai, T. Kawai, K. Matsushita, A. Hiiragi, T. S. Dermody, T. Fujita, and S. Akira. 2008. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med. 205: 1601-1610.
58. Proietti, E., L. Bracci, S. Puzelli, T. Di Pucchio, P. Sestili, E. De Vincenzi, M. Venditti, I. Capone, I. Seif, E. De Maeyer, et al. 2002. Type I IFN as a natural adjuvant for a protective immune response: lessons from the influenza vaccine model. J. Immunol. 169: 375-383.
59. Rizza, P., I. Capone, F. Moretti, E. Proietti, and F. Belardelli. 2011. IFN-a as a vaccine adjuvant: recent insights into the mechanisms and perspectives for its clinical use. Expert Rev. Vaccines 10: 487-498.
60. Kasturi, S. P., I. Skountzou, R. A. Albrecht, D. Koutsonanos, T. Hua, H. I. Nakaya, R. Ravindran, S. Stewart, M. Alam, M. Kwissa, et al. 2011. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470: 543-547.
61. Mutwiri, G., V. Gerdts, S. van Drunen Littel-van den Hurk, G. Auray, N. Eng, S. Garlapati, L. A. Babiuk, and A. Potter. 2011. Combination adjuvants: the next generation of adjuvants? Expert Rev. Vaccines 10: 95-107.
62. Zhu, Q., C. Egelston, S. Gagnon, Y. Sui, I. M. Belyakov, D. M. Klinman, and J. A. Berzofsky. 2010. Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J. Clin. Invest. 120: 607-616.
63. Didierlaurent, A. M., S. Morel, L. Lockman, S. L. Giannini, M. Bisteau, H. Carlsen, A. Kielland, O. Vosters, N. Vanderheyde, F. Schiavetti, et al. 2009. AS04, an aluminum salt-and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J. Immunol. 183: 6186-6197.
64. Plotkin, S. A. 2008. Vaccines: correlates of vaccine-induced immunity. Clin. Infect. Dis. 47: 401-409.
65. Swanson, C. L., T. J. Wilson, P. Strauch, M. Colonna, R. Pelanda, and R. M. Torres. 2010. Type I IFN enhances follicular B cell contribution to the T cell-independent antibody response. J. Exp. Med. 207: 1485-1500.
66. McKee, A. S., M. W. Munks, and P. Marrack. 2007. How do adjuvants work? Important considerations for new generation adjuvants. Immunity 27: 687-690.