Archives of Virology

, Volume 156, Issue 2, pp 183–202 | Cite as

Adjuvants and delivery systems in veterinary vaccinology: current state and future developments

  • Peter M. H. Heegaard
  • Laurence Dedieu
  • Nicholas Johnson
  • Marie-Frédérique Le Potier
  • Michael Mockey
  • Franco Mutinelli
  • Thomas Vahlenkamp
  • Marta Vascellari
  • Nanna Skall Sørensen
Brief Review


Modern adjuvants should induce strong and balanced immune responses, and it is often desirable to induce specific types of immunity. As an example, efficient Th1-immunity-inducing adjuvants are highly in demand. Such adjuvants promote good cell-mediated immunity against subunit vaccines that have low immunogenicity themselves. The development of such adjuvants may take advantage of the increased knowledge of the molecular mechanisms and factors controlling these responses. However, knowledge of such molecular details of immune mechanisms is relatively scarce for species other than humans and laboratory rodents, and in addition, there are special considerations pertaining to the use of adjuvants in veterinary animals, such as production and companion animals. With a focus on veterinary animals, this review highlights a number of approaches being pursued, including cytokines, CpG oligonucleotides, microparticles and liposomes.


Local Reaction Bovine Viral Diarrhoea Virus Bovine Leukemia Virus Mucosal Immune Response Intranasal Delivery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by the EU Network of Excellence, EPIZONE (Contract No FOOD-CT-2006-016236).

Supplementary material

705_2010_863_MOESM1_ESM.pdf (822 kb)
Supplementary material (PDF 821 kb)


  1. 1.
    Aguilar JC, Rodriguez EG (2007) Vaccine adjuvants revisited. Vaccine 25:3752–3762PubMedCrossRefGoogle Scholar
  2. 2.
    Aich P, Wilson HL, Kaushik RS, Potter AA, Babiuk LA, Griebel P (2007) Comparative analysis of innate immune responses following infection of newborn calves with bovine rotavirus and bovine coronavirus. J Gen Virol 88:2749–2761PubMedCrossRefGoogle Scholar
  3. 3.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell R (2001) Recognition of double-stranded RNA and activation of NF-kB by toll-like receptor 3. Nature 413:732–738PubMedCrossRefGoogle Scholar
  4. 4.
    Alves MP, Guzylack-Piriou L, Juillard V, Audonnet JC, Doel T, Dawson H, Golde WT, Gerber H, Peduto N, McCullough KC, Summerfield A (2009) Innate immune defenses induced by CpG do not promote vaccine-induced protection against foot-and-mouth disease virus in pigs. Clin Vaccine Immunol 16:1151–1157PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson KV, Bokla L, Nüsslein-Volhard C (1985) Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 42:791–798PubMedCrossRefGoogle Scholar
  6. 6.
    Aramaki Y, Suda H, Tsuchiya S (1995) Interferon-gamma inductive effect of liposomes as an immunoadjuvant. Vaccine 13(18):1809–1814PubMedCrossRefGoogle Scholar
  7. 7.
    Arany I, Tyring SK, Brysk MM, Stanley MA, Tomai MA, Miller RL, Smith MH, McDermott DJ, Slade HB (2000) Correlation between pre-treatment levels of interferon response genes and clinical responses to an immune response modifier (Imiquimod) in genital warts. Antimicrob Agents Chemother 44:1869–1873PubMedCrossRefGoogle Scholar
  8. 8.
    Aucouturier J, Dupuis L, Ganne V (2001) Adjuvants designed for veterinary and human vaccines. Vaccine 19:2666–2672PubMedCrossRefGoogle Scholar
  9. 9.
    Baca-Estrada ME, Foldvari M, Snider M, van Drunen Littel-van den Hurk S, Babiuk LA (1997) Effect of IL4 and IL-12 liposomal formulations on the induction of immune response to bovine herpesvirus type-1 glycoprotein D. Vaccine 15(16):1753–1760PubMedCrossRefGoogle Scholar
  10. 10.
    Ballow M, Wang X, Xiang S, Allen C (2003) Expression and regulation of nuclear retinoic acid receptors in human lymphoid cells. J Clin Immunol 23:46–54PubMedCrossRefGoogle Scholar
  11. 11.
    Barton GM, Medzhitov R (2003) Linking Toll-like receptors to IFN-a/b expression. Nat Immunol 4:432–433PubMedCrossRefGoogle Scholar
  12. 12.
    Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM (2003) Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol 24:528–533PubMedCrossRefGoogle Scholar
  13. 13.
    Belyakov IM, Ahlers JD, Berkofsky JA (2004) Mucosal AIDS vaccines: current status and future directions. Expert Rev Vaccines 3:S65–S73PubMedCrossRefGoogle Scholar
  14. 14.
    Beutner KR, Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM Jr (1998) Treatment of genital warts with an immune-response modifier (Imiquimod). J Am Acad Dermatol 38:230–239PubMedCrossRefGoogle Scholar
  15. 15.
    Bollinger JN (1970) Metabolic fate of mineral oil adjuvants using 14C-labeled tracers I: mineral oil. J Pharm Sci 59:1084–1088PubMedCrossRefGoogle Scholar
  16. 16.
    Booth JS, Nichani AK, Benjamin P, Dar A, Krieg AM, Babiuk LA, Mutwiri GK (2007) Innate immune responses induced by classes of CpG oligodeoxynucleotides in ovine lymph and blood mononuclear cells. Vet Immunol Immunopathol 115:24–34PubMedCrossRefGoogle Scholar
  17. 17.
    Bowersock TL, HogenEsch H, Toregrosa S, Borie D, Wang B, Park H, Park K (1998) Induction of pulmonary immunity in cattle by oral administration of ovalbumin in alginate microspheres. Immunol Lett 60:37–43PubMedCrossRefGoogle Scholar
  18. 18.
    Brandhonneur N, Chevanne F, Vié V, Frisch B, Primault R, Le Potier MF, Le Corre P (2009) Specific and non-specific phagocytosis of ligand-grafted PLGA microspheres by macrophages. Eur J Pharm Sci 36:474–485PubMedCrossRefGoogle Scholar
  19. 19.
    Brown WC, Estes DM, Chantler SE, Kegerreis KA, Suarez CE (1998) DNA and a CpG oligonucleotide derived from Babesia bovis are mitogenic for bovine B cells. Infect Immun 66:5423–5432PubMedGoogle Scholar
  20. 20.
    Campos M, Godson DL (2003) The effectiveness and limitations of immune memory: understanding protective immune responses. Int J Parasitol 33:655–661PubMedCrossRefGoogle Scholar
  21. 21.
    Cargill EJ, Womack JE (2007) Detection of polymorphisms in bovine toll-like receptors 3, 7, 8 and 9. Genomics 89:745–755PubMedCrossRefGoogle Scholar
  22. 22.
    Charerntantanakul W (2009) Adjuvants for porcine reproductive and respiratory syndrome virus vaccines. Vet Immunol Immunopathol 129:1–13PubMedCrossRefGoogle Scholar
  23. 23.
    Choe J, Kelker MS, Wilson IA (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309:581–585PubMedCrossRefGoogle Scholar
  24. 24.
    Creagh EM, O’Neill LA (2006) TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 27:352–357PubMedCrossRefGoogle Scholar
  25. 25.
    Czerkinsky C, Anjuere F, McGhee JR, George-Chandy A, Holmgren J, Kieny MP, Fujiyashi K, Mestecky JF, Pierrefite-Carle V, Rask C, Sun JB (1999) Mucosal immunity and tolerance: relevance to vaccine development. Immunol Rev 170:197–222PubMedCrossRefGoogle Scholar
  26. 26.
    Dalsgaard K, Hilgers L, Trouve G (1990) Classical and new approaches to adjuvant use in domestic food animals. Adv Vet Sci Comp Med 35:121–128PubMedGoogle Scholar
  27. 27.
    Dar A, Nichani AK, Benjamin P, Lai K, Soita H, Krieg AM, Potter A, Babiuk LA, Mutwiri GK (2008) Attenuated cytokine responses in porcine lymph node cells stimulated with CpG DNA are associated with low frequency of IFN-alpha-producing cells and TLR9 expression. Vet Immunol Immunopathol 123:324–336PubMedCrossRefGoogle Scholar
  28. 28.
    DeCicco KL, Zolfaghari R, Li N-Q, Ross AC (2000) Retinoic acid and polyriboinosinic acid act synergistically to enhance the antibody response to tetanus toxoid during vitamin A deficiency: possible involvement of interleukin-2 receptor-beta, signal transducer and activator of transcription-1, and interferon regulatory factor-1. J Infect Dis 182(Supp 1):S29–S36PubMedCrossRefGoogle Scholar
  29. 29.
    Dempsey PW, Vaidya SA, Cheng G (2003) The art of war: Innate and adaptive immune responses. Cell Mol Life Sci 60:2604–2621PubMedCrossRefGoogle Scholar
  30. 30.
    Dory D, Béven V, Torché AM, Bougeard S, Cariolet R, Jestin A (2005) CpG motif in ATCGAT hexamer improves DNA-vaccine efficiency against lethal Pseudorabies virus infection in pigs. Vaccine 23:4532–4540PubMedCrossRefGoogle Scholar
  31. 31.
    Dudda JC, Lembo A, Bachtanian E, Huehn J, Siewert C, Hamann A, Kremmer E, Förster R, Martin SF (2005) Dendritic cells govern induction and reprogramming of polarized tissue-selective homing receptor patterns of T cells: important roles for soluble factors and tissue microenvironments. Eur J Immunol 35:1056–1065PubMedCrossRefGoogle Scholar
  32. 32.
    Dudda JC, Martin SF (2004) Tissue targeting of T cells by DCs and microenvironments. Trends Immunol 25:417–421PubMedCrossRefGoogle Scholar
  33. 33.
    Edelmann KH, Richardson-Burns S, Alexopoulou L, Tyler KL, Flavell RA, Oldstone MBA (2004) Does Toll-like receptor 3 play a biological role in virus infections? Virology 322:231–238PubMedCrossRefGoogle Scholar
  34. 34.
    Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453:1122–1126PubMedCrossRefGoogle Scholar
  35. 35.
    Einer-Jensen K, Delgado L, Lorenzen E, Bovo G, Evensen Ø, Lapatra S, Lorenzen N (2009) Dual DNA vaccination of rainbow trout (Oncorhynchus mykiss) against two different rhabdoviruses, VHSV and IHNV, induces specific divalent protection. Vaccine 27:1248–1253PubMedCrossRefGoogle Scholar
  36. 36.
    Enjoutina EY, Visic D, Daynes RA (2000) The induction of systemic and mucosal immune responses to antigen-adjuvant compositions administered into the skin: alterations in the migratory properties of dendritic cells appears to be important for stimulating mucosal immunity. Vaccine 18:2753–2767CrossRefGoogle Scholar
  37. 37.
    Felder CB, Vorlaender N, Gander B, Merkle HP, Bertschinger HU (2000) Microencapsulated enterotoxigenic Escherichia coli and detached fimbriae for peroral vaccination of pigs. Vaccine 19:706–715PubMedCrossRefGoogle Scholar
  38. 38.
    Fenner F, Pastoret P-P, Blancou J, Terré J (1997) Historical Introduction. In: Pastoret P-P, Blancou J, Verschueren C (eds) Veterinary vaccinology. Elsevier, Amsterdam, pp 3–19Google Scholar
  39. 39.
    Flohr F, Schneider-Schaulies S, Haller O, Kochs G (1999) The central interactive region of human MxA GTPase is involved in GTPase activation and interaction with viral target structures. FEBS Lett 463:24–28PubMedCrossRefGoogle Scholar
  40. 40.
    Foged C, Arigita C, Sundblad A, Jiskoot W, Storm G, Frokjaer S (2004) Interaction of dendritic cells with antigen-containing liposomes: effect of bilayer composition. Vaccine 22:1903–1913PubMedCrossRefGoogle Scholar
  41. 41.
    Franchini M, Scheizer M, Matzener P, Maghouras I, Sauter K-S, Mirkovitch J, Peterhans E, Jungi TW (2006) Evidence for dissociation of TLR mRNA expression and TLR agonist-mediated functions in bovine macrophages. Vet Immunol Immunopathol 110:37–49PubMedCrossRefGoogle Scholar
  42. 42.
    Fraser CK, Diener KR, Brown MP, Hayball JD (2007) Improving vaccines by incorporating immunological coadjuvants. Expert Rev Vaccines 6:559–578PubMedCrossRefGoogle Scholar
  43. 43.
    Fukanoki S, Matsumoto K, Mori H, Takeda R (2000) Effect of liquid paraffin on antibody responses and local adverse reactions of bivalent oil adjuvanted vaccines containing newcastle disease virus and infectious bronchitis virus. J Vet Med Sci 62:1317–1319PubMedCrossRefGoogle Scholar
  44. 44.
    Gangur V, Birmingham NP, Thanesvorakul S (2002) Chemokines in health and disease. Vet Immunol Immunopathol 86:127–136PubMedCrossRefGoogle Scholar
  45. 45.
    Gerdts V, Mutwiri GK, Tikoo SK, Babiuk LA (2006) Mucosal delivery of vaccines in domestic animals. Vet Res 37:487–510PubMedCrossRefGoogle Scholar
  46. 46.
    Goldammer T, Zerbe H, Molenaar A, Schuberth HJ, Brunner RM, Kata SR, Seyfert HM (2004) Mastitis increases mammary mRNA abundance of b-defensin 5, toll-like receptor 2 (TLR2) and TLR4 but not TLR9 in cattle. Clin Diagn Lab Immunol 11:174–185PubMedGoogle Scholar
  47. 47.
    Griebel PJ, Broenlie R, Manuja A, Nichani A, Mookherjee N, Popowych Y, Mutwiri G, Hecker R, Babiuk LA (2005) Bovine toll-like receptor 9: a comparative analysis of molecular structure, function and expression. Vet Immunol Immunopathol 108:11–16PubMedCrossRefGoogle Scholar
  48. 48.
    Guy B (2007) The perfect mix: recent progress in adjuvant research. Nat Rev Microbiol 5:505–517PubMedCrossRefGoogle Scholar
  49. 49.
    Guzylack-Piriou L, Balmelli C, McCullough KC, Summerfield A (2004) Type-A CpG oligonucleotides activate exclusively porcine natural interferon-producing cells to secrete interferon-alpha, tumour necrosis factor-alpha and interleukin-12. Immunology. 112:28–37PubMedCrossRefGoogle Scholar
  50. 50.
    Hargis AM, Ginn PE (2007) The integument. In: MacGavin MD, Zachary JF (eds) Pathological basis of veterinary disease, 4th edn. Mosby Elsevier, St Louis, pp 1167–1168Google Scholar
  51. 51.
    Harpin S, Hurley DJ, Mbikay M, Talbot B, Elazhary Y (1999) Vaccination of cattle with a DNA plasmid encoding the bovine viral diarrhoea virus major glycoprotein E2. J Gen Virol 80(Pt 12):3137–3144PubMedGoogle Scholar
  52. 52.
    Hattori Y, Kawakami S, Suzuki S, Yamashita F, Hashida M (2004) Enhancement of immune responses by DNA vaccination through targeted gene delivery using mannosylated cationic liposome formulations following intravenous administration in mice. Biochem Biophys Res Commun 317(4):992–999PubMedCrossRefGoogle Scholar
  53. 53.
    Hendrick MJ, Brooks JJ (1994) Postvaccinal sarcomas in the cat: histology and immunohistochemistry. Vet Pathol 31:126–129PubMedCrossRefGoogle Scholar
  54. 54.
    Immordino ML, Dosio F, Cattel L (2006) Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomed 1(3):297–315CrossRefGoogle Scholar
  55. 55.
    Iwasaki A (2007) Mucosal dendritic cells. Annu Rev Immunol 25:381–418PubMedCrossRefGoogle Scholar
  56. 56.
    Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song S (2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21:527–538PubMedCrossRefGoogle Scholar
  57. 57.
    Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54(Pt 1):1–13PubMedGoogle Scholar
  58. 58.
    Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216PubMedCrossRefGoogle Scholar
  59. 59.
    Jansen T, Hofmans MPM, Theelen MJG, Manders F, Schijns VEJC (2006) Structure- and oil type-based efficacy of emulsion adjuvants. Vaccine 24:5400–5405PubMedCrossRefGoogle Scholar
  60. 60.
    Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J (2003) Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin-6. Immunity 19:225–234PubMedCrossRefGoogle Scholar
  61. 61.
    Jelinek FE (2003) Postinflammatory sarcoma in cats. Exp Toxicol Pathol 55:167–172PubMedCrossRefGoogle Scholar
  62. 62.
    Jiang H, Kang M, Quan J, Kang S, Akaike T, Yoo H, Cho CS (2008) The potential of mannosylated chitosan microspheres to target macrophage mannose receptors in an adjuvant delivery system for intranasal immunization. Biomaterials 29:1931–1939PubMedCrossRefGoogle Scholar
  63. 63.
    Johansson-Lindbom B, Svensson M, Wurbel M-A, Malissen B, Márquez G, Agace W (2003) Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J Exp Med 198:963–969PubMedCrossRefGoogle Scholar
  64. 64.
    Kakuda T, Sugimoto C, Onuma M (2001) Epitope-mapping of antigen-specific T lymphocyte in cattle immunized with recombinant major piroplasm surface protein of Theileria sergenti. J Vet Med Sci 63(8):895–901PubMedCrossRefGoogle Scholar
  65. 65.
    Kamstrup S, Verthelyi D, Klinman DM (2001) Response of porcine peripheral blood mononuclear cells to CpG-containing oligodeoxynucleotides. Vet Microbiol 78:353–362PubMedCrossRefGoogle Scholar
  66. 66.
    Kamstrup S, Frimann TH, Barfoed AM (2006) Protection of Balb/c mice against infection with FMDV by immunostimulation with CpG oligonucleotides. Antiviral Res 72:42–48PubMedCrossRefGoogle Scholar
  67. 67.
    Kang M, Kang S, Jiang H, Guo D, Lee D, Rayamahji N, Seo Y, Cho C, Yoo H (2008) Chitosan microspheres containing Bordetella bronchiseptica antigens as novel vaccine against atrophic rhinitis in pigs. J Microbiol Biotechnol 18:1179–1185PubMedGoogle Scholar
  68. 68.
    Kapsenberg ML (2003) Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3:984–993PubMedCrossRefGoogle Scholar
  69. 69.
    Kass PH, Barnes WG Jr, Spangler WL, Chomel BB, Culbertson MR (1993) Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 203:396–405PubMedGoogle Scholar
  70. 70.
    Kass PH, Spangler WL, Hendrick MJ, McGill LD, Esplin DG, Lester S, Slater M, Meyer EK, Boucher F, Peters EM, Gobar GG, Htoo T, Decile K (2003) Multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats. J Am Vet Med Assoc 223:1283–1292PubMedCrossRefGoogle Scholar
  71. 71.
    Kaufmann SHE (2007) The contribution of immunology to the rational design of novel antibacterial vaccines. Nat Rev Microbiol 5:491–504PubMedCrossRefGoogle Scholar
  72. 72.
    Kavanagh OV, Earley B, Murray M, Foster CJ, Adair BM (2003) Antigen-specific IgA and IgG responses in calves inoculated intranasally with ovalbumin encapsulated in poly(dl-lactide-co-glycolide) microspheres. Vaccine 21:4472–4480PubMedCrossRefGoogle Scholar
  73. 73.
    Kekarainen T, Montoya M, Dominguez J, Mateu E, Segalés J (2008) Porcine circovirus type 2 (PCV2) viral components immunomodulate recall antigen responses. Vet Immunol Immunopathol 124:41–49PubMedCrossRefGoogle Scholar
  74. 74.
    Kieny MP, Girard MP (2005) Human vaccine research and development: an overview. Vaccine 23:5705–5707PubMedCrossRefGoogle Scholar
  75. 75.
    Kim B, Bowersock T, Griebel P, Kidane A, Babiuk LA, Sanchez M, Attah-Poku S, Kaushik RS, Mutwiri GK (2002) Mucosal immune responses following oral immunization with rotavirus antigens encapsulated in alginate microspheres. J Control Release 85:191–202PubMedCrossRefGoogle Scholar
  76. 76.
    Kim CH, Johnson MC, Drennan JD, Simon BE, Thomann E, Leong JA (2000) DNA vaccines encoding viral glycoproteins induce nonspecific immunity and Mx protein synthesis in fish. J Virol 74:7048–7054PubMedCrossRefGoogle Scholar
  77. 77.
    Klinman DM, Kamstrup S, Verthelyi D, Gursel I, Ishii KJ, Takeshita F, Gursel M (2000) Activation of the innate immune system by CpG oligodeoxynuclotides: immunoprotective activity and safety. Springer Semim Immunopathol 22:173–183CrossRefGoogle Scholar
  78. 78.
    Klinman DM, Currie D, Shirota H (2007) Immunostimulatory CpG oligodeoxynucleotides as vaccine adjuvants. In: Singh M (ed) Vaccine adjuvants and delivery systems. Wiley, London, pp 157–174CrossRefGoogle Scholar
  79. 79.
    Koppang EO, Haugarvoll E, Hordvik I, Aune L, Poppe T (2005) Vaccine-associated granulomatous inflammation and melanin accumulation in Atlantic salmon, Salmo salar L, white muscle. J Fish Dis 28:13–22PubMedCrossRefGoogle Scholar
  80. 80.
    Kovacs-Nolan J, Mapletoft JW, Latimer L, Babiuk LA, Hurk SD (2009) CpG oligonucleotide, host defense peptide and polyphosphazene act synergistically, inducing long-lasting, balanced immune responses in cattle. Vaccine 27:2048–2054PubMedCrossRefGoogle Scholar
  81. 81.
    Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549PubMedCrossRefGoogle Scholar
  82. 82.
    Krieg AM (2002) CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709–760PubMedCrossRefGoogle Scholar
  83. 83.
    Kringel H, Dubey JP, Beshah E, Hecker R, Urban JF Jr (2004) CpG-oligodeoxynucleotides enhance porcine immunity to Toxoplasma gondii. Vet Parasitol 123:55–66PubMedCrossRefGoogle Scholar
  84. 84.
    Krug A, Rothenfusser S, Hornung V, Jahrsdörfer B, Blackwell S, Ballas ZK, Endres S, Krieg AM, Hartmann G (2001) Identification of CpG oligonucleotide sequences with high induction of IFN-α/β in plasmacytoid dendritic cells. Eur J Immunol 31:2154–2163PubMedCrossRefGoogle Scholar
  85. 85.
    Lampen A, Meyer S, Arnhold T, Nau H (2000) Metabolism of vitamin A and its active metabolite all-trans-retinoic acid in small intestinal enterocytes. J Pharmacol Exp Ther 295:979–985PubMedGoogle Scholar
  86. 86.
    Lanzavecchia A, Sallusto F (2001) Regulation of T cell immunity by dendritic cells. Cell 106:263–266PubMedCrossRefGoogle Scholar
  87. 87.
    Laval A, Ganne V, Aucouturier J, Crespeau F, Levy D (1996) Efficacy and safety of new adjuvanted vaccine formulations containing inactivated exotoxin antigens from Pasteurella multocida. In: Proceedings of the 14th IPVS Congress, Bologna 1996Google Scholar
  88. 88.
    Laval A, Ganne V, Aucouturier J, Deville S, Levy D (1998) Assessment of a new adjuvant range in a model for atrophic rhinitis. In: Proceedings of the 15th IPVS congress, Birmingham 1998Google Scholar
  89. 89.
    Le Bon A, Schiavoni G, D’Agostin G, Gresser I, Belardelli F, Tough DF (2001) Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14:461–470PubMedCrossRefGoogle Scholar
  90. 90.
    Lee SR, Pharr GT, Boyd BL, Pinchuk LM (2008) Bovine viral diarrhea viruses modulate toll-like receptors, cytokines and co-stimulatory molecules genes expression in bovine peripheral blood monocytes. Comp Immunol Microbiol Infect Dis 31:403–418PubMedCrossRefGoogle Scholar
  91. 91.
    Leserman L, Barois N (1998) Major histocompatibility complex class II molecules, liposomes and antigen presentation. In: Lasic DD, Papahadjopoulos D (eds) Medical applications of Liposomes. Elsevier, Amsterdam, pp 25–45CrossRefGoogle Scholar
  92. 92.
    Liebler-Tenorio EM, Pabst R (2006) MALT structure and function in farm animals. Vet Res 37:257–280PubMedCrossRefGoogle Scholar
  93. 93.
    Lin JH, Weng CN, Liao CW, Yeh KS, Pan MJ (2003) Protective effects of oral microencapsulated Mycoplasma hyopneumoniae vaccine prepared by co-spray drying method. J Vet Med Sci 65:69–74PubMedCrossRefGoogle Scholar
  94. 94.
    Lindblad EB (2007) Safety evaluation of vaccine adjuvants. In: Singh M (ed) Vaccine adjuvants and delivery systems. Wiley, London, pp 421–444CrossRefGoogle Scholar
  95. 95.
    Linghua Z, Xingshan T, Fengzhen Z (2008) In vivo oral administration effects of various oligodeoxynucleotides containing synthetic immunostimulatory motifs in the immune response to pseudorabies attenuated virus vaccine in newborn piglets. Vaccine 26:224–233PubMedCrossRefGoogle Scholar
  96. 96.
    Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale MW, Iwasaki A, Flavell RA (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 101:5598–5603PubMedCrossRefGoogle Scholar
  97. 97.
    Mallick AI, Singha H, Chaudhuri P, Nadeem A, Khan SA, Dar KA, Owais M (2007) Liposomised recombinant ribosomal L7/L12 protein protects BALB/c mice against Brucella abortus 544 infection. Vaccine 25(18):3692–3704PubMedCrossRefGoogle Scholar
  98. 98.
    Marr AK, Kurzman ID, Vail DM (2004) Preclinical evaluation of a liposome-encapsulated formulation of cisplatin in clinically normal dogs. Am J Vet Res 65(11):1474–1478PubMedCrossRefGoogle Scholar
  99. 99.
    Maruyama K (2002) PEG-immunoliposome. Biosci Rep 22(2):251–266PubMedCrossRefGoogle Scholar
  100. 100.
    Matsumoto M, Funami K, Oshiumi H, Seya T (2004) Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. Microbiol Immunol 48:147–154PubMedGoogle Scholar
  101. 101.
    Matsushima N, Tanaka T, Enchbayar P, Mikami T, Taga M, Yamada K, Kuroki Y (2007) Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors. BMC Genomics 8:124–144PubMedCrossRefGoogle Scholar
  102. 102.
    McKimmie CS, Johnson N, Fooks AR, Fazakerley JK (2005) Viruses selectively upregulate Toll-like receptors in the central nervous system. Biochem Biophys Res Commun 336:925–933PubMedCrossRefGoogle Scholar
  103. 103.
    Mena A, Nichani AK, Popowych Y, Ioannou XP, Godson DL, Mutwiri GK, Hecker R, Babiuk LA (2003) Bovine and ovine blood mononuclear leukocytes differ markedly in innate immune responses induced by class A and class B CpG-oligodeoxynucleotides. Oligonucleotides 13:245–259PubMedCrossRefGoogle Scholar
  104. 104.
    Menzies M, Ingham A (2005) Identification and expression of Toll-like receptors 1–10 in selected bovine and ovine tissue. Vet Immunol Immunopathol 109:23–30PubMedCrossRefGoogle Scholar
  105. 105.
    Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, von Andrian UH (2003) Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424:88–93PubMedCrossRefGoogle Scholar
  106. 106.
    Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, Adams DH, von Andrian UH (2006) Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 17:1157–1160CrossRefGoogle Scholar
  107. 107.
    Morton DB (2007) Vaccines and animal welfare. Rev Sci Tech 26:157–163PubMedGoogle Scholar
  108. 108.
    Mullin D (2003) Prometheus in Gloucestershire: Edward Jenner, 1749–1823. J Allergy Clin Immunol 112:810–814PubMedCrossRefGoogle Scholar
  109. 109.
    Munday JS, Stedman NL, Richey LJ (2003) Histology and immunohistochemistry of seven ferret vaccination-site fibrosarcomas. Vet Pathol 40:288–293PubMedCrossRefGoogle Scholar
  110. 110.
    Muneta Y, Uenishi H, Kikuma R, Yoshihara K, Shimoji Y, Yamamoto R, Hamashima N, Yokomizo Y, Mori Y (2003) Porcine TLR2 and TLR6: identification and their involvement in Mycoplasma hyopneumoniae infection. J Interferon Res 23:583–590CrossRefGoogle Scholar
  111. 111.
    Murphy PM (2001) Viral exploitation and subversion of the immune system through chemokine mimicry. Nat Immunol 2:116–122PubMedCrossRefGoogle Scholar
  112. 112.
    Mutwiri G, Bowersock T, Kidane A, Sanchez M, Gerdts V, Babieuk LA, Griebel P (2002) Induction of mucosal immune response following enteric immunization with antigen delivered in alginate microspheres. Vet Immunol Immunopathol 87:269–276PubMedCrossRefGoogle Scholar
  113. 113.
    Mutwiri GK, Nichani AK, Babiuk S, Babiuk LA (2004) Strategies for enhancing the immunostimulatory effects of CpG oligodeoxynucleotides. J Control Release 97:1–17PubMedCrossRefGoogle Scholar
  114. 114.
    Niborski V, Li Y, Brennan F, Lane M, Torche AM, Remond M, Bonneau M, Riffault S, Stirling C, Hutchings G, Takamatsu H, Barnett P, Charley B, Schwartz-Cornil I (2006) Efficacy of particle-based DNA delivery for vaccination of sheep against FMDV. Vaccine 24:7204–7213PubMedCrossRefGoogle Scholar
  115. 115.
    Nichani AK, Dar MA, Krieg AM, Mirakhur KK, Kaushik RS, Griebel PJ, Manuja A, Townsend HGG, Babiuk LA, Mutwiri GK (2007) Systemic innate immune responses following intrapulmonary delivery og CpG oligodeoxynucleotides in sheep. Vet Immunol Immunopathol 115:357–368PubMedCrossRefGoogle Scholar
  116. 116.
    Normile D (2008) Rinderpest driven to extinction. Science 319:1606–1609PubMedCrossRefGoogle Scholar
  117. 117.
    O’Brien CN, Guidry AJ, Douglass LW, Westhoff DC (2001) Immunization with Staphylococcus aureus lysate incorporated into microspheres. J Dairy Sci 84:1791–1799PubMedCrossRefGoogle Scholar
  118. 118.
    Ortega-Villaizan M, Chico V, Falco A, Perez L, Coll JM, Estepa A (2009) The rainbow trout TLR9 gene and its role in the immune responses elicited by a plasmid encoding the glycoprotein G of the viral haemorrhagic septicaemia rhabdovirus (VHSV). Mol Immunol 46:1710–1717PubMedCrossRefGoogle Scholar
  119. 119.
    Ott G, van Nest G (2007) Development of vaccine adjuvants: a historical perspective. In: Singh M (ed) Vaccine adjuvants and delivery systems. Wiley, London, pp 1–31CrossRefGoogle Scholar
  120. 120.
    Pasare C, Medzhitov R (2004) Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 6:1382–1387PubMedCrossRefGoogle Scholar
  121. 121.
    Patel JR, Heldens JGM (2009) Immunoprophylaxis against important virus diseases of horses, farm animals and birds. Vaccine 27:1797–1810PubMedCrossRefGoogle Scholar
  122. 122.
    Poirier VJ, Thamm DH, Kurzman ID, Jeglum KA, Chun R, Obradovich JE, O’Brien M, Fred RM 3rd, Phillips BS, Vail DM (2002) Liposome-encapsulated doxorubicin (Doxil) and doxorubicin in the treatment of vaccine-associated sarcoma in cats. J Vet Intern Med 16(6):726–731PubMedCrossRefGoogle Scholar
  123. 123.
    Poppe TT, Barnes AC, Midtlyng P (2002) Welfare and ethics in fish farming. Bull Eur Ass Fish Pathol 22:148–151Google Scholar
  124. 124.
    Proietti E, Bracci L, Puzelli S, Di Pucchio T, Sestill P, De Vincenzi E, Venditti M, Capone I, Seif I, De Maeyer E, Tough D, Donatelli I, Belardelli F (2002) Type I IFN as a natural adjuvant for a productive immune response: lessons from the influenza vaccine model. J Immunol 169:375–383PubMedGoogle Scholar
  125. 125.
    Pulendran B, Ahmed R (2006) Translating innate immunity into immunological memory: implications for vaccine development. Cell 124:849–863PubMedCrossRefGoogle Scholar
  126. 126.
    Rebelatto MC, Guimond P, Bowersock TL, HogenEsch H (2001) Induction of systemic and mucosal immune response in cattle by intranasal administration of pig serum albumin in alginate microparticles. Vet Immunol Immunopathol 83(1–2):93–105PubMedCrossRefGoogle Scholar
  127. 127.
    Richards JR, Elston TH, Ford RB, Gaskell RM, Hartmann K, Hurley KF, Lappin MR, Levy JK, Rodan I, Scherk M, Schultz RD, Sparkes AH (2006) The 2006 American Association of Feline Practitioners Feline Vaccine Advisory Panel Report. J Am Vet Med Ass 229:1405–1441CrossRefGoogle Scholar
  128. 128.
    Rock KL, Hearn A, Chen CJ, Shi Y (2005) Natural endogenous adjuvants. Springer Semin Immunopathol 26:231–246PubMedCrossRefGoogle Scholar
  129. 129.
    Roth JA (1999) Mechanistic bases for adverse vaccine reactions and vaccine failures. Adv Vet Med 41:681–700PubMedCrossRefGoogle Scholar
  130. 130.
    Rughetti A, Biffoni M, Sabbatucci M, Rahimi H, Pellicciotta I, Fattorossi A, Pierelli L, Scambia G, Lavitrano M, Frati L, Nuti M (2000) Transfected human dendritic cells to induce antitumor immunity. Gene Ther 7(17):1458–1466PubMedCrossRefGoogle Scholar
  131. 131.
    Ruma guidelines Responsible use of vaccines and vaccinations in farm animal production. Responsible use of medicines in agriculture alliance. Welwyn, 2006, pp 1–31.
  132. 132.
    Saurer L, McCullough KC, Summerfield A (2007) In vitro induction of mucosa-type dendritic cells by all-trans retinoic acid. J Immunol 179:3504–3514PubMedGoogle Scholar
  133. 133.
    Scicchitano R, Husband AJ, Clancy RL (1984) Contribution of intraperitoneal immunization to the local immune response in the respiratory tract of sheep. Immunology 53(2):375–384PubMedGoogle Scholar
  134. 134.
    Singh M, O’Hagan DT (2003) Recent advances in veterinary vaccine adjuvants. Int J Parasitol 33:469–478PubMedCrossRefGoogle Scholar
  135. 135.
    Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521PubMedCrossRefGoogle Scholar
  136. 136.
    Skountzou I, Quan F-S, Jacob J, Compans RW, Kang S-M (2006) Transcutaneous immunization with inactivated influenza virus induces protective immune responses. Vaccine 24:6110–6119PubMedCrossRefGoogle Scholar
  137. 137.
    Spickler AR, Roth JA (2003) Adjuvants in veterinary vaccines: modes of action and adverse effects. J Vet Intern Med 17:273–281PubMedCrossRefGoogle Scholar
  138. 138.
    Stagg AJ, Kamm MA, Knight SC (2002) Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin. Eur J Immunol 32:1445–1454PubMedCrossRefGoogle Scholar
  139. 139.
    Stanley AC, Huntley JF, Jeffrey M, Buxton D (2001) Characterization of ovine nasal-associated lymphoid tissue and identification of M cells in the overlying follicle-associated epithelium. J Comp Pathol 125:262–270PubMedCrossRefGoogle Scholar
  140. 140.
    Steinman RM, Hemmi H (2006) Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 311:17–58PubMedCrossRefGoogle Scholar
  141. 141.
    Stills HF (2005) Adjuvants and antibody production: dispelling the myths associated with Freund’s complete and other adjuvants. ILAR J 46:280–293PubMedGoogle Scholar
  142. 142.
    Tabeta K, Georgl P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, Alexopoulou L, Flavell RA, Beutler B (2004) Toll-like receptors 9 and 3 as essential components of innate immune defence against mouse cytomegalovirus. Proc Natl Acad Sci USA 101:3516–3521PubMedCrossRefGoogle Scholar
  143. 143.
    Tana WS, Lee JT, Onuma M, Ochiai K, Kakidani H, Yasuda T (1997) In vivo antitumor effect of cationic liposomes containing diphtheria toxin A-chain gene on cells infected with bovine leukemia virus. J Vet Med Sci 59(7):617–619PubMedCrossRefGoogle Scholar
  144. 144.
    Thiele L, Rothen-Rutishauser B, Jilek S, Wunderli-Allenspach H, Merkle HP, Walter E (2001) Evaluation of particle uptake in human blood monocyte-derived cells in vitro. Does phagocytosis activity of dendritic cells measure up with macrophages? J Control Release 76(1–2):59–71PubMedCrossRefGoogle Scholar
  145. 145.
    Tokunaga T, Yamamoto H, Shimada S, Abe H, Fukuda T, Fujisawa Y, Furutani Y, Yano O, Kataoka T, Sudo T et al (1984) Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. J Natl Cancer Inst 72:955–962PubMedGoogle Scholar
  146. 146.
    Torche AM, Albina E, Lecorre P, Jestin A, Leverge R (1999) Flow cytometric and optical microscopic evaluation of poly(d,l-lactide-co-glycolide) microspheres phagocytosis by pig alveolar macrophages. J Control Release 58:289–301PubMedCrossRefGoogle Scholar
  147. 147.
    Torche AM, Jouan H, Le Corre P, Albina E, Primault R, Jestin A, Le Verge R (2000) Ex vivo and in situ PLGA microspheres uptake by pig ileal Peyer’s patch segment. Int J Pharm 201:15–27PubMedCrossRefGoogle Scholar
  148. 148.
    Torche AM, Lecorre P, Albina E, Jestin A, Leverge R (2000) PLGA microspheres phagocytosis by pig alveolar macrophages: influence of poly(vinyl alcohol) concentration, nature of loaded-protein and copolymer nature. J Drug Target 7:343–354PubMedCrossRefGoogle Scholar
  149. 149.
    Torche AM, Le Dimna M, Le Corre P, Mesplede A, Le Gal S, Cariolet R, Le Potier MF (2006) Immune responses after local administration of IgY loaded-PLGA microspheres in gut-associated lymphoid tissue in pigs. Vet Immunol Immunopathol 109:209–217PubMedCrossRefGoogle Scholar
  150. 150.
    Tovey M, Lallemand C, Meritet J-F, Maury C (2006) Adjuvant activity of interferon alpha: mechanism(s) of action. Vaccine 24:S2/46-47Google Scholar
  151. 151.
    U’Ren LW, Biller BJ, Elmslie RE, Thamm DH, Dow SW (2007) Evaluation of a novel tumor vaccine in dogs with hemangiosarcoma. J Vet Intern Med 21(1):113–120PubMedCrossRefGoogle Scholar
  152. 152.
    Van der Stede Y, Verdonck F, Vancaeneghem S, Cox E, Goddeeris BM (2002) CpG-oligodinucleotides as an effective adjuvant in pigs for intramuscular immunizations. Vet Immunol Immunopathol 86:31–41PubMedCrossRefGoogle Scholar
  153. 153.
    van Drunen Littel-van den Hurk S, Babiuk SL, Babiuk LA (2004) Strategies for improved formulation and delivery of DANN vaccines to veterinary targets species. Immunol Rev 199:113–125PubMedCrossRefGoogle Scholar
  154. 154.
    Vascellari M, Melchiotti E, Bozza MA, Mutinelli F (2003) Fibrosarcomas at presumed sites of injection in dogs: characteristics and comparison with non-vaccination site fibrosarcomas and feline post-vaccinal fibrosarcomas. J Vet Med A 50:286–291CrossRefGoogle Scholar
  155. 155.
    Verfaillie T, Cox E, Goddeeris BM (2005) Immunostimulatory capacity of DNA vaccine vectors in porcine PBMC: a specific role for CpG-motifs? Vet Immunol Immunopathol 103:141–151PubMedCrossRefGoogle Scholar
  156. 156.
    Verthelyi D, Ishii KJ, Gursel M, Takeshita F, Klinman DM (2001) Human peripheral blood cells differentially recognize and respond to two distinct CpG motifs. J Immunol 166:2372–2377PubMedGoogle Scholar
  157. 157.
    Weng CN, Tzan YL, Liu SD, Lin SY, Lee CJ (1992) Protective effects of an oral microencapsulated Mycoplasma hyopneumoniae vaccine against experimental infection in pigs. Res Vet Sci 53:42–46PubMedCrossRefGoogle Scholar
  158. 158.
    Werling D, Hope JC, Howard CJ, Jungi TW (2004) Differential production of cytokines, reactive oxygen and nitrogen by bovine macrophages and dendritic cells stimulated with Toll-like receptor agonists. Immunology 11:41–52CrossRefGoogle Scholar
  159. 159.
    Werling D, Coffey TJ (2007) Pattern recognition receptors in companion and farm animals—the key to unlocking the door to animal disease? Vet J 174:240–251PubMedCrossRefGoogle Scholar
  160. 160.
    Wille-Reece U, Flynn BJ, Lore K, Koup RA, Miles AP, Saul A, Kedl RM, Mattapallil JJ, Weiss WR, Roederer M, Seder RA (2006) Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates. J Exp Med 203:1249–1258PubMedCrossRefGoogle Scholar
  161. 161.
    Wills-Karp M (2007) Complement activation pathways: a bridge between innate and adaptive immune responses in asthma. Proc Am Thorac Soc 4:247–251PubMedCrossRefGoogle Scholar
  162. 162.
    Xiang SD, Scholzen A, Minigo G, David C, Apostolopoulos V, Mottram PL, Plebanski M (2006) Pathogen recognition and development of particulate vaccines: does size matter? Methods 40:1–9PubMedCrossRefGoogle Scholar
  163. 163.
    Yu H, Babiuk LA, van Drunen Littel-van den Hurk S (2004) Priming with CpG-enriched plasmid and boosting with protein formulated with CpG oligodeoxynucleotides and Quil A induces strong cellular and humoral immune responses to hepatitis C virus NS3. J Gen Virol 85:1533–1543PubMedCrossRefGoogle Scholar
  164. 164.
    Zaks K, Jordan M, Guth A, Sellins K, Kedl R, Izzo A, Bosio C, Dow S (2006) Efficient immunization and cross-priming by vaccine adjuvants containing TLR3 or TLR9 agonists complexed to cationic liposomes. J Immunol 176:7335–7345PubMedGoogle Scholar
  165. 165.
    Zhou F, Neutra MR (2002) Antigen delivery to mucosa-associated lymphoid tissues using liposomes as a carrier. Biosci Rep 22(2):355–369CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Peter M. H. Heegaard
    • 1
  • Laurence Dedieu
    • 2
  • Nicholas Johnson
    • 3
  • Marie-Frédérique Le Potier
    • 4
  • Michael Mockey
    • 2
  • Franco Mutinelli
    • 5
  • Thomas Vahlenkamp
    • 6
  • Marta Vascellari
    • 5
  • Nanna Skall Sørensen
    • 1
  1. 1.Department of Veterinary Diagnostics and Research, National Veterinary InstituteTechnical University of DenmarkCopenhagen VDenmark
  2. 2.CIRAD, UMR CMAEE Contrôle des Maladies AnimalesMontpellierFrance
  3. 3.Veterinary Laboratories Agency, New HawSurreyUK
  4. 4.Anses Laboratoire de PloufraganUnité virologie et immunologie porcinesPloufraganFrance
  5. 5.Histopathology DepartmentIstituto Zooprofilattico Sperimentale delle VenezieLegnaro (PD)Italy
  6. 6.Friedrich-Loeffler-Institute, Federal Research Institute for Animal HealthGreifswald-Insel RiemsGermany

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