1887

Abstract

Respiratory syncytial virus (RSV) is the leading cause of serious respiratory tract disease in children and calves; however, RSV vaccine development has been slow due to early observations that formalin-inactivated vaccines induced Th2-type immune responses and led to disease enhancement upon subsequent exposure. Hence, there is a need for novel adjuvants that will promote a protective Th1-type or balanced immune response against RSV. CpG oligodeoxynucleotides (ODNs), indolicidin, and polyphosphazene were examined for their ability to enhance antigen-specific immune responses and influence the Th-bias when co-formulated with a recombinant truncated bovine RSV (BRSV) fusion protein (ΔF). Mice immunized with ΔF co-formulated with CpG ODN, indolicidin, and polyphosphazene (ΔF/CpG/indol/PP) developed higher levels of ΔF-specific serum IgG, IgG1 and IgG2a antibodies when compared with ΔF alone, and displayed an increase in the frequency of gamma interferon-secreting cells and decreased interleukin (IL)-5 production by restimulated splenocytes, characteristic of a Th1 immune response. These results were observed in both C57BL/6 and BALB/c strains of mice. When evaluated in a BRSV challenge model, mice immunized with ΔF/CpG/indol/PP developed significantly higher levels of BRSV-neutralizing serum antibodies than mice immunized with the ΔF protein alone, and displayed significantly less pulmonary IL-4, IL-5, IL-13 and eotaxin and reduced eosinophilia after challenge. These results suggest that co-formulation of ΔF with CpG ODN, host defence peptide and polyphosphazene may result in a safe and effective vaccine for the prevention of BRSV and may have implications for the development of novel human RSV vaccines.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.011684-0
2009-08-01
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/90/8/1892.html?itemId=/content/journal/jgv/10.1099/vir.0.011684-0&mimeType=html&fmt=ahah

References

  1. Alwan W. H., Record F. M., Openshaw P. J. 1992; CD4+ T cells clear virus but augment disease in mice infected with respiratory syncytial virus. Comparison with the effects of CD8+ T cells. Clin Exp Immunol 88:527–536
    [Google Scholar]
  2. An L. L., Yang Y. H., Ma X. T., Lin Y. M., Li G., Song Y. H., Wu K. F. 2005; LL-37 enhances adaptive antitumor immune response in a murine model when genetically fused with M-CSFRJ6-1 DNA vaccine. Leuk Res 29:535–543 [CrossRef]
    [Google Scholar]
  3. Andrianov A. K., Svirkin Y. Y., LeGolvan M. P. 2004; Synthesis and biologically relevant properties of polyphosphazene polyacids. Biomacromolecules 5:1999–2006 [CrossRef]
    [Google Scholar]
  4. Andrianov A. K., Marin A., Roberts B. E. 2005; Polyphosphazene polyelectrolytes: a link between the formation of noncovalent complexes with antigenic proteins and immunostimulating activity. Biomacromolecules 6:1375–1379 [CrossRef]
    [Google Scholar]
  5. Antonis A. F., Schrijver R. S., Daus F., Steverink P. J., Stockhofe N., Hensen E. J., Langedijk J. P., Van Der Most R. G. 2003; Vaccine-induced immunopathology during bovine respiratory syncytial virus infection: exploring the parameters of pathogenesis. J Virol 77:12067–12073 [CrossRef]
    [Google Scholar]
  6. Baca-Estrada M. E., Snider M., Tikoo S. K., Harland R., Babiuk L. A., van Drunen Littel-van den Hurk S. 1996; Immunogenicity of bovine herpesvirus 1 glycoprotein D in mice: effect of antigen form on the induction of cellular and humoral immune responses. Viral Immunol 9:11–22 [CrossRef]
    [Google Scholar]
  7. Bangham C. R., Openshaw P. J., Ball L. A., King A. M., Wertz G. W., Askonas B. A. 1986; Human and murine cytotoxic T cells specific to respiratory syncytial virus recognize the viral nucleoprotein (N), but not the major glycoprotein (G), expressed by vaccinia virus recombinants. J Immunol 137:3973–3977
    [Google Scholar]
  8. Bowdish D. M., Davidson D. J., Scott M. G., Hancock R. E. 2005; Immunomodulatory activities of small host defense peptides. Antimicrob Agents Chemother 49:1727–1732 [CrossRef]
    [Google Scholar]
  9. Brown K. L., Hancock R. E. 2006; Cationic host defense (antimicrobial) peptides. Curr Opin Immunol 18:24–30 [CrossRef]
    [Google Scholar]
  10. Cannon M. J., Openshaw P. J., Askonas B. A. 1988; Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med 168:1163–1168 [CrossRef]
    [Google Scholar]
  11. Castilow E. M., Meyerholz D. K., Varga S. M. 2008; IL-13 is required for eosinophil entry into the lung during respiratory syncytial virus vaccine-enhanced disease. J Immunol 180:2376–2384 [CrossRef]
    [Google Scholar]
  12. Collins P. L., Crowe J. E. Jr 2007; Respiratory syncytial virus and metapneumovirus. In Fields Virology , 5th edn. vol 2p– 1601Edited by Knipe D. M., Howley. Philadelphia: Lippincott Williams & Wilkins;
    [Google Scholar]
  13. Collins P. L., Huang Y. T., Wertz G. W. 1984; Nucleotide sequence of the gene encoding the fusion (F) glycoprotein of human respiratory syncytial virus. Proc Natl Acad Sci U S A 81:7683–7687 [CrossRef]
    [Google Scholar]
  14. Davis H. L., Weeratna R., Waldschmidt T. J., Tygrett L., Schorr J., Krieg A. M. 1998; CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J Immunol 160:870–876
    [Google Scholar]
  15. Delgado M. F., Coviello S., Monsalvo A. C., Melendi G. A., Hernandez J. Z., Batalle J. P., Diaz L., Trento A., Chang H. Y. other authors 2009; Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat Med 15:34–41 [CrossRef]
    [Google Scholar]
  16. de Waal L., Suzer Y., Wyatt L. S., Sintnicolaas K., Sutter G., Moss B., Osterhaus A. D., de Swart R. L. 2006; T cell responses to respiratory syncytial virus fusion and attachment proteins in human peripheral blood mononuclear cells. Viral Immunol 19:669–678 [CrossRef]
    [Google Scholar]
  17. Durbin J. E., Johnson T. R., Durbin R. K., Mertz S. E., Morotti R. A., Peebles R. S., Graham B. S. 2002; The role of IFN in respiratory syncytial virus pathogenesis. J Immunol 168:2944–2952 [CrossRef]
    [Google Scholar]
  18. Fenton C., Scott L. J., Plosker G. L. 2004; Palivizumab: a review of its use as prophylaxis for serious respiratory syncytial virus infection. Paediatr Drugs 6:177–197 [CrossRef]
    [Google Scholar]
  19. Fritz J. H., Brunner S., Birnstiel M. L., Buschle M., Gabain A., Mattner F., Zauner W. 2004; The artificial antimicrobial peptide KLKLLLLLKLK induces predominantly a Th2-type immune response to co-injected antigens. Vaccine 22:3274–3284 [CrossRef]
    [Google Scholar]
  20. Gershwin L. J. 2007; Bovine respiratory syncytial virus infection: immunopathogenic mechanisms. Anim Health Res Rev 8:207–213 [CrossRef]
    [Google Scholar]
  21. Glezen W. P., Taber L. H., Frank A. L., Kasel J. A. 1986; Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 140:543–546
    [Google Scholar]
  22. Graham B. S., Johnson T. R., Peebles R. S. 2000; Immune-mediated disease pathogenesis in respiratory syncytial virus infection. Immunopharmacology 48:237–247 [CrossRef]
    [Google Scholar]
  23. Hall C. B., Walsh E. E., Long C. E., Schnabel K. C. 1991; Immunity to and frequency of reinfection with respiratory syncytial virus. J Infect Dis 163:693–698 [CrossRef]
    [Google Scholar]
  24. Hancock R. E. 2001; Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infect Dis 1:156–164 [CrossRef]
    [Google Scholar]
  25. Hancock G. E., Hahn D. J., Speelman D. J., Hildreth S. W., Pillai S., McQueen K. 1994; The pulmonary immune response of BALB/c mice vaccinated with the fusion protein of respiratory syncytial virus. Vaccine 12:267–274 [CrossRef]
    [Google Scholar]
  26. Hancock G. E., Speelman D. J., Frenchick P. J., Mineo-Kuhn M. M., Baggs R. B., Hahn D. J. 1995; Formulation of the purified fusion protein of respiratory syncytial virus with the saponin QS-21 induces protective immune responses in BALB/c mice that are similar to those generated by experimental infection. Vaccine 13:391–400 [CrossRef]
    [Google Scholar]
  27. Hancock G. E., Heers K. M., Smith J. D., Scheuer C. A., Ibraghimov A. R., Pryharski K. S. 2001; CpG containing oligodeoxynucleotides are potent adjuvants for parenteral vaccination with the fusion (F) protein of respiratory syncytial virus (RSV). Vaccine 19:4874–4882 [CrossRef]
    [Google Scholar]
  28. Ioannou X. P., Gomis S. M., Karvonen B., Hecker R., Babiuk L. A., van Drunen Littel-van den Hurk S. 2002; CpG-containing oligodeoxynucleotides, in combination with conventional adjuvants, enhance the magnitude and change the bias of the immune responses to a herpesvirus glycoprotein. Vaccine 21:127–137 [CrossRef]
    [Google Scholar]
  29. Isaacs D. 1991; Viral subunit vaccines. Lancet 337:1223–1224 [CrossRef]
    [Google Scholar]
  30. Johnson P. R., Collins P. L. 1988; The fusion glycoproteins of human respiratory syncytial virus of subgroups A and B: sequence conservation provides a structural basis for antigenic relatedness. J Gen Virol 69:2623–2628 [CrossRef]
    [Google Scholar]
  31. Johnson T. R., Parker R. A., Johnson J. E., Graham B. S. 2003; IL-13 is sufficient for respiratory syncytial virus G glycoprotein-induced eosinophilia after respiratory syncytial virus challenge. J Immunol 170:2037–2045 [CrossRef]
    [Google Scholar]
  32. Klinman D. M. 2004; Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4:249–258 [CrossRef]
    [Google Scholar]
  33. Klinman D. M., Yi A. K., Beaucage S. L., Conover J., Krieg A. M. 1996; CpG motifs present in bacterial DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon γ . Proc Natl Acad Sci U S A 93:2879–2883 [CrossRef]
    [Google Scholar]
  34. Klinman D. M., Barnhart K. M., Conover J. 1999; CpG motifs as immune adjuvants. Vaccine 17:19–25 [CrossRef]
    [Google Scholar]
  35. Kovacs-Nolan J., Latimer L., Landi A., Jenssen H., Hancock R. E. W., Babiuk L. A., van Drunen Littel-van den Hurk S. 2009; The novel adjuvant combination of CpG ODN, indolicidin and polyphosphazene induces potent antibody- and cell-mediated immune responses in mice. Vaccine 27:2055–2064 [CrossRef]
    [Google Scholar]
  36. Krieg A. M. 2006; Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 5:471–484 [CrossRef]
    [Google Scholar]
  37. Krieg A. M., Yi A. K., Matson S., Waldschmidt T. J., Bishop G. A., Teasdale R., Koretzky G. A., Klinman D. M. 1995; CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549 [CrossRef]
    [Google Scholar]
  38. Kurosaka K., Chen Q., Yarovinsky F., Oppenheim J. J., Yang D. 2005; Mouse cathelin-related antimicrobial peptide chemoattracts leukocytes using formyl peptide receptor-like 1/mouse formyl peptide receptor-like 2 as the receptor and acts as an immune adjuvant. J Immunol 174:6257–6265 [CrossRef]
    [Google Scholar]
  39. Laemmli U. K. 1970; Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685 [CrossRef]
    [Google Scholar]
  40. Lingnau K., Egyed A., Schellack C., Mattner F., Buschle M., Schmidt W. 2002; Poly-l-arginine synergizes with oligodeoxynucleotides containing CpG-motifs (CpG-ODN) for enhanced and prolonged immune responses and prevents the CpG-ODN-induced systemic release of pro-inflammatory cytokines. Vaccine 20:3498–3508 [CrossRef]
    [Google Scholar]
  41. Lopez J. A., Bustos R., Orvell C., Berois M., Arbiza J., Garcia-Barreno B., Melero J. A. 1998; Antigenic structure of human respiratory syncytial virus fusion glycoprotein. J Virol 72:6922–6928
    [Google Scholar]
  42. Mapletoft J. W., Oumouna M., Kovacs-Nolan J., Latimer L., Mutwiri G., Babiuk L. A., van Drunen Littel-van den Hurk S. 2008; Intranasal immunization of mice with a formalin-inactivated bovine respiratory syncytial virus vaccine co-formulated with CpG oligodeoxynucleotides and polyphosphazenes results in enhanced protection. J Gen Virol 89:250–260 [CrossRef]
    [Google Scholar]
  43. McCluskie M. J., Krieg A. M. 2006; Enhancement of infectious disease vaccines through TLR9-dependent recognition of CpG DNA. Curr Top Microbiol Immunol 311:155–178
    [Google Scholar]
  44. McNeal M. M., Rae M. N., Ward R. L. 1999; Effects of different adjuvants on rotavirus antibody responses and protection in mice following intramuscular immunization with inactivated rotavirus. Vaccine 17:1573–1580 [CrossRef]
    [Google Scholar]
  45. Meyer G., Deplanche M., Schelcher F. 2008; Human and bovine respiratory syncytial virus vaccine research and development. Comp Immunol Microbiol Infect Dis 31:191–225 [CrossRef]
    [Google Scholar]
  46. Muelenaer P. M., Henderson F. W., Hemming V. G., Walsh E. E., Anderson L. J., Prince G. A., Murphy B. R. 1991; Group-specific serum antibody responses in children with primary and recurrent respiratory syncytial virus infections. J Infect Dis 164:15–21 [CrossRef]
    [Google Scholar]
  47. Mutwiri G., Benjamin P., Soita H., Townsend H., Yost R., Roberts B., Andrianov A. K., Babiuk L. A. 2007; Poly[di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP) is a potent enhancer of mixed Th1/Th2 immune responses in mice immunized with influenza virus antigens. Vaccine 25:1204–1213 [CrossRef]
    [Google Scholar]
  48. Palframan R. T., Collins P. D., Williams T. J., Rankin S. M. 1998; Eotaxin induces a rapid release of eosinophils and their progenitors from the bone marrow. Blood 91:2240–2248
    [Google Scholar]
  49. Payne L. G., Andrianov A. K. 1998; Protein release from polyphosphazene matrices. Adv Drug Deliv Rev 31:185–196 [CrossRef]
    [Google Scholar]
  50. Payne L. G., Jenkins S. A., Woods A. L., Grund E. M., Geribo W. E., Loebelenz J. R., Andrianov A. K., Roberts B. E. 1998; Poly[di(carboxylatophenoxy)phosphazene] (PCPP) is a potent immunoadjuvant for an influenza vaccine. Vaccine 16:92–98 [CrossRef]
    [Google Scholar]
  51. Perrie Y., Mohammed A. R., Kirby D. J., McNeil S. E., Bramwell V. W. 2008; Vaccine adjuvant systems: enhancing the efficacy of sub-unit protein antigens. Int J Pharm 364:272–280 [CrossRef]
    [Google Scholar]
  52. Polack F. P., Teng M. N., Collins P. L., Prince G. A., Exner M., Regele H., Lirman D. D., Rabold R., Hoffman S. J. other authors 2002; A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med 196:859–865 [CrossRef]
    [Google Scholar]
  53. Prince G. A., Mond J. J., Porter D. D., Yim K. C., Lan S. J., Klinman D. M. 2003; Immunoprotective activity and safety of a respiratory syncytial virus vaccine: mucosal delivery of fusion glycoprotein with a CpG oligodeoxynucleotide adjuvant. J Virol 77:13156–13160 [CrossRef]
    [Google Scholar]
  54. Rankin S. M., Conroy D. M., Williams T. J. 2000; Eotaxin and eosinophil recruitment: implications for human disease. Mol Med Today 6:20–27 [CrossRef]
    [Google Scholar]
  55. Selsted M. E., Novotny M. J., Morris W. L., Tang Y. Q., Smith W., Cullor J. S. 1992; Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils. J Biol Chem 267:4292–4295
    [Google Scholar]
  56. Shay D. K., Holman R. C., Newman R. D., Liu L. L., Stout J. W., Anderson L. J. 1999; Bronchiolitis-associated hospitalizations among US children, 1980–1996. JAMA 282:1440–1446 [CrossRef]
    [Google Scholar]
  57. Sigurs N., Bjarnason R., Sigurbergsson F., Kjellman B., Bjorksten B. 1995; Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics 95:500–505
    [Google Scholar]
  58. Sigurs N., Bjarnason R., Sigurbergsson F., Kjellman B. 2000; Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 161:1501–1507 [CrossRef]
    [Google Scholar]
  59. Srikiatkhachorn A., Braciale T. J. 1997; Virus-specific CD8+ T lymphocytes downregulate T helper cell type 2 cytokine secretion and pulmonary eosinophilia during experimental murine respiratory syncytial virus infection. J Exp Med 186:421–432 [CrossRef]
    [Google Scholar]
  60. Taylor G., Stott E. J., Bew M., Fernie B. F., Cote P. J., Collins A. P., Hughes M., Jebbett J. 1984; Monoclonal antibodies protect against respiratory syncytial virus infection in mice. Immunology 52:137–142
    [Google Scholar]
  61. Valarcher J. F., Taylor G. 2007; Bovine respiratory syncytial virus infection. Vet Res 38:153–180 [CrossRef]
    [Google Scholar]
  62. van der Poel W. H., Brand A., Kramps J. A., Van Oirschot J. T. 1994; Respiratory syncytial virus infections in human beings and in cattle. J Infect 29:215–228 [CrossRef]
    [Google Scholar]
  63. Viuff B., Tjornehoj K., Larsen L. E., Rontved C. M., Uttenthal A., Ronsholt L., Alexandersen S. 2002; Replication and clearance of respiratory syncytial virus: apoptosis is an important pathway of virus clearance after experimental infection with bovine respiratory syncytial virus. Am J Pathol 161:2195–2207 [CrossRef]
    [Google Scholar]
  64. Walsh E. E. 1994; Humoral, mucosal, and cellular immune response to topical immunization with a subunit respiratory syncytial virus vaccine. J Infect Dis 170:345–350 [CrossRef]
    [Google Scholar]
  65. Walsh E. E., Schlesinger J. J., Brandriss M. W. 1984; Protection from respiratory syncytial virus infection in cotton rats by passive transfer of monoclonal antibodies. Infect Immun 43:756–758
    [Google Scholar]
  66. Waris M. E., Tsou C., Erdman D. D., Zaki S. R., Anderson L. J. 1996; Respiratory syncytial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induces enhanced pulmonary inflammatory response with a predominant Th2-like cytokine pattern. J Virol 70:2852–2860
    [Google Scholar]
  67. Wu J. Y., Wade W. F., Taylor R. K. 2001; Evaluation of cholera vaccines formulated with toxin-coregulated pilin peptide plus polymer adjuvant in mice. Infect Immun 69:7695–7702 [CrossRef]
    [Google Scholar]
  68. Zimmer G., Conzelmann K. K., Herrler G. 2002; Cleavage at the furin consensus sequence RAR/KR(109) and presence of the intervening peptide of the respiratory syncytial virus fusion protein are dispensable for virus replication in cell culture. J Virol 76:9218–9224 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.011684-0
Loading
/content/journal/jgv/10.1099/vir.0.011684-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error