Skip to main content

Subunit Vaccine Candidates Engineered from the Central Conserved Region of the RSV G Protein Aimed for Parenteral or Mucosal Delivery

  • Chapter
  • First Online:
Molecular Vaccines

Abstract

Respiratory syncytial virus (RSV) is a major pathogen causing severe upper and lower respiratory disease in infants and in elderly worldwide. According to WHO, an RSV vaccine is urgently needed. Here, we describe the design of various types of subunit vaccine concepts based on molecular engineering aimed to deliver RSV antigens. Gene segment encoding parts of the conserved central region of the RSV G protein (G2Na) were prepared for various expression and delivery formats: (1) prokaryotically expressed and purified G2Na alone or fused to different carrier proteins, one of them, namely, BBG2Na (Alum), has reached clinical trials in the elderly; (2) G protein-derived antigens surface displayed on lived vectors (non pathogenic bacteria) and (3) nucleic acid vectors.

These subunit vaccines were administered with or without adjuvant in rodents and in non-human primates by different routes (parenteral or mucosal). We summarise and compare immunogenicity, protective efficacy and safety conferred by each immunisation format in RSV experimental animal models. Among these, G2Na proved to be the most promising component for an RSV subunit vaccine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Andersson, C., Liljestrom, P., Stahl, S., Power, U.F.: Protection against RSV elicited in mice by plasmid DNA immunisation encoding a secreted RSV G protein-derived antigen. FEMS Immunol. Med. Microbiol. 29, 247–253 (2000)

    Article  PubMed  CAS  Google Scholar 

  2. Beck, A., et al.: Synthesis and characterization of RSV protein G related peptides containing two disulfide bridges. J. Pept. Res. 55, 24–35 (2000)

    Article  PubMed  CAS  Google Scholar 

  3. Blanco, J.C., Boukhvalova, M.S., Shirey, K.A., Prince, G.A., Vogel, S.N.: New insights for development of a safe and protective RSV vaccine. Hum. Vaccin. 6, 482–492 (2010)

    Article  PubMed  CAS  Google Scholar 

  4. Brandt, C., et al.: Protective immunity against RSV in early life after murine maternal or neonatal vaccination with the recombinant G fusion protein BBG2Na. J. Infect. Dis. 176, 884–891 (1997)

    Article  PubMed  CAS  Google Scholar 

  5. Bukreyev, A., et al.: The cysteine-rich region and secreted form of the attachment G glycoprotein of RSV enhance the cytotoxic T-lymphocyte response despite lacking major histocompatibility complex class I-restricted epitopes. J. Virol. 80, 5854–5861 (2006)

    Article  PubMed  CAS  Google Scholar 

  6. Cannon, M.J., Openshaw, P.J., Askonas, B.A.: Cytotoxic T cells clear virus but augment lung pathology in mice infected with RSV. J. Exp. Med. 168, 1163–1168 (1988)

    Article  PubMed  CAS  Google Scholar 

  7. Cano, F., et al.: A surface-displayed cholera toxin B peptide improves antibody responses using food-grade staphylococci for mucosal subunit vaccine delivery. FEMS Immunol. Med. Microbiol. 25, 289–298 (1999)

    Article  PubMed  CAS  Google Scholar 

  8. Cano, F., et al.: Partial protection to RSV elicited in mice by intranasal immunization using live staphylococci with surface-displayed RSV-peptides. Vaccine 18, 2743–2752 (2000)

    Article  PubMed  CAS  Google Scholar 

  9. Chang, J.: Current progress on development of RSV vaccine. BMB Rep. 44, 232–237 (2011)

    Article  PubMed  CAS  Google Scholar 

  10. Choi, Y., et al.: Antibodies to the central conserved region of respiratory syncytial virus (RSV) G protein block RSV G protein CX3C-CX3CR1 binding and cross-neutralize RSV A and B strains. Viral Immunol. 25, 193–203 (2012)

    PubMed  CAS  Google Scholar 

  11. Collins, P.L., Crowe, J.E., Jr.: Respiratory syncytial virus and metapneumovirus. In D.M. Knipe and P.M. Howley (eds.), Fields Virology. Lippincott Williams & Wilkins, Philadelphia, Vol. 2. 5th ed. 1601–1646 (2007)

    Google Scholar 

  12. Connors, M., et al.: Resistance to RSV challenge induced by infection with a vaccinia virus recombinant expressing the RSV M2 protein (Vac-M2) is mediated by CD8+ T cells, while that induced by Vac-F or Vac-G recombinants is mediated by antibodies. J. Virol. 66, 1277–1281 (1992)

    PubMed  CAS  Google Scholar 

  13. Corvaia, N., et al.: Challenge of BALB/c mice with RSV does not enhance the Th2 pathway induced after immunization with a recombinant G fusion protein, BBG2Na, in aluminum hydroxide. J. Infect. Dis. 176, 560–569 (1997)

    Article  PubMed  CAS  Google Scholar 

  14. de Bree, G.J., et al.: Respiratory syncytial virus-specific CD8+ memory T cell responses in elderly persons. J. Infect. Dis. 191, 1710–1718 (2005)

    Article  PubMed  Google Scholar 

  15. de Waal, L., et al.: Evaluation of BBG2Na in infant macaques: specific immune responses after vaccination and RSV challenge. Vaccine 22, 915–922 (2004)

    Article  PubMed  Google Scholar 

  16. Delgado, M.F., et al.: Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced RSV disease. Nat. Med. 15, 34–41 (2009)

    Article  PubMed  CAS  Google Scholar 

  17. Delmas, A., Partidos, C.D.: The binding of chimeric peptides to GM1 ganglioside enables induction of antibody responses after intranasal immunization. Vaccine 14, 1077–1082 (1996)

    Article  PubMed  CAS  Google Scholar 

  18. Falcone, V., et al.: Systemic and mucosal immunity to RSV induced by recombinant Streptococcus gordonii surface-displaying a domain of viral glycoprotein G. FEMS Immunol. Med. Microbiol. 48, 116–122 (2006)

    Article  PubMed  CAS  Google Scholar 

  19. Falsey, A.R., et al.: RSV and influenza A infections in the hospitalized elderly. J. Infect. Dis. 172, 389–394 (1995)

    Article  PubMed  CAS  Google Scholar 

  20. Feldman, S.A., Hendry, R.M., Beeler, J.A.: Identification of a linear heparin binding domain for human RSV attachment glycoprotein G. J. Virol. 73, 6610–6617 (1999)

    PubMed  CAS  Google Scholar 

  21. Godefroy, S., et al.: Immunization onto shaved skin with a bacterial enterotoxin adjuvant protects mice against RSV. Vaccine 21, 1665–1671 (2003)

    Article  PubMed  CAS  Google Scholar 

  22. Goetsch, L., et al.: Influence of administration dose and route on the immunogenicity and protective efficacy of BBG2Na, a recombinant RSV subunit vaccine candidate. Vaccine 18, 2735–2742 (2000)

    Article  PubMed  CAS  Google Scholar 

  23. Goetsch, L., et al.: BBG2Na an RSV subunit vaccine candidate intramuscularly injected to human confers protection against viral challenge after nasal immunization in mice. Vaccine 19, 4036–4042 (2001)

    Article  PubMed  CAS  Google Scholar 

  24. Haeuw, J.F., et al.: The recombinant Klebsiella pneumoniae outer membrane protein OmpA has carrier properties for conjugated antigenic peptides. Eur. J. Biochem. 255, 446–454 (1998)

    Article  PubMed  CAS  Google Scholar 

  25. Harcourt, J., et al.: RSV G protein and G protein CX3C motif adversely affect CX3CR1+ T cell responses. J. Immunol. 176, 1600–1608 (2006)

    PubMed  CAS  Google Scholar 

  26. Huang, Y., Anderson, R.: A single amino acid substitution in a recombinant G protein vaccine drastically curtails protective immunity against RSV. Vaccine 21, 2500–2505 (2003)

    Article  PubMed  CAS  Google Scholar 

  27. Isaacs, D., Bangham, C.R., McMichael, A.J.: Cell-mediated cytotoxic response to RSV in infants with bronchiolitis. Lancet 2, 769–771 (1987)

    Article  PubMed  CAS  Google Scholar 

  28. Jang, J.E., et al.: Evaluation of protective efficacy of RSV vaccine against A and B subgroup human isolates in Korea. PLoS One 6, e23797 (2011)

    Article  PubMed  CAS  Google Scholar 

  29. Kim, S., Chang, J.: Baculovirus-based vaccine displaying RSV glycoprotein induces protective immunity against RSV infection without vaccine-enhanced disease. Immune. Netw. 12, 8–17 (2012)

    Article  PubMed  Google Scholar 

  30. Kim, S., et al.: Dual role of RSV glycoprotein fragment as a mucosal immunogen and chemotactic adjuvant. PLoS One 7, e32226 (2012)

    Article  PubMed  CAS  Google Scholar 

  31. Klinguer-Hamour, C., et al.: DDA adjuvant induces a mixed Th1/Th2 immune response when associated with BBG2Na, a RSV potential vaccine. Vaccine 20, 2743–2751 (2002)

    Article  PubMed  CAS  Google Scholar 

  32. Klinguer-Hamour, C., et al.: Synthesis, refolding and protective immune responses of a potential antigen for human RSV vaccine. J. Pept. Res. 62, 27–36 (2003)

    Article  PubMed  CAS  Google Scholar 

  33. Klinguer, C., et al.: Lipophilic quaternary ammonium salt acts as a mucosal adjuvant when co-administered by the nasal route with vaccine antigens. Vaccine 19, 4236–4244 (2001)

    Article  PubMed  CAS  Google Scholar 

  34. Le Cam, N.B., et al.: Safety and immunogenicity of BBG2Na a RSV subunit vaccine based on G derived recombinant protein in the elderly: a phase II study. In: 40th ICAAC meeting. Toronto. 21–26 Sept 1999

    Google Scholar 

  35. Libon, C., et al.: The serum albumin-binding region of Streptococcal protein G (BB) potentiates the immunogenicity of the G130-230 RSV-A protein. Vaccine 17, 406–414 (1998)

    Article  Google Scholar 

  36. Libon, C., et al.: Identification of the component responsible for the type III hypersensitivity reaction (HS III) induced by BBG2Na, a subunit RSV vaccine. In: Poster – Sixth International RSV meeting, Marco Island, FL, 25–28 Oct 2007

    Google Scholar 

  37. Liljeqvist, S., et al.: Surface display of the cholera toxin B subunit on Staphylococcus xylosus and Staphylococcus carnosus. Appl. Environ. Microbiol. 63, 2481–2488 (1997)

    PubMed  CAS  Google Scholar 

  38. Liljeqvist, S., et al.: Fusions to the cholera toxin B subunit: influence on pentamerization and GM1 binding. J. Immunol. Methods 210, 125–135 (1997)

    Article  PubMed  CAS  Google Scholar 

  39. Liljeqvist, S., et al.: Surface display of functional fibronectin-binding domains on Staphylococcus carnosus. FEBS Lett. 446, 299–304 (1999)

    Article  PubMed  CAS  Google Scholar 

  40. Liljeqvist, S., Stahl, S.: Production of recombinant subunit vaccines: protein immunogens, live delivery systems and nucleic acid vaccines. J. Biotechnol. 73, 1–33 (1999)

    Article  PubMed  CAS  Google Scholar 

  41. Melendi, G.A., et al.: Conserved cysteine residues within the attachment G glycoprotein of RSV play a critical role in the enhancement of cytotoxic T-lymphocyte responses. Virus Genes 42, 46–54 (2011)

    Article  PubMed  CAS  Google Scholar 

  42. Munoz, F.M., Piedra, P.A., Glezen, W.P.: Safety and immunogenicity of RSV purified fusion protein-2 vaccine in pregnant women. Vaccine 21, 3465–3467 (2003)

    Article  PubMed  CAS  Google Scholar 

  43. Murata, Y., Catherman, S.C.: Antibody response to the central unglycosylated region of the RSV attachment protein in mice. Vaccine 30, 5382–5388 (2012)

    Article  PubMed  CAS  Google Scholar 

  44. Nguyen, T.N., Libon, C.: G2Na & BBG2Na. Unpublished

    Google Scholar 

  45. Nguyen, T.N., et al.: Cell-surface display of heterologous epitopes on Staphylococcus xylosus as a potential delivery system for oral vaccination. Gene 128, 89–94 (1993)

    Article  PubMed  CAS  Google Scholar 

  46. Nguyen, T.N., et al.: Hydrophobicity engineering to facilitate surface display of heterologous gene products in Staphylococcus xylosus. J. Biotechnol. 42, 207–219 (1995)

    Article  PubMed  CAS  Google Scholar 

  47. Nguyen, T.N., et al.: Chromosomal sequencing using a PCR-based biotin-capture method allowed isolation of the complete gene for the outer membrane protein A of Klebsiella pneumoniae. Gene 210, 93–101 (1998)

    Article  PubMed  CAS  Google Scholar 

  48. Nguyen, T.N., et al.: The RSV G protein conserved domain induces a persistent and protective antibody response in rodents. PLoS One 7, e34331 (2012)

    Article  PubMed  CAS  Google Scholar 

  49. Nygren, P.A., Eliasson, M., Abrahmsen, L., Uhlen, M., Palmcrantz, E.: Analysis and use of the serum albumin binding domains of streptococcal protein G. J. Mol. Recognit. 1, 69–74 (1988)

    Article  PubMed  CAS  Google Scholar 

  50. Nygren, P.A., Uhlen, M., Flodby, P., Wigzell, H.: In vivo stabilization of human recombinant CD4 derivative by fusion to a serum-albumin-binding receptor. Vaccines 91 Cold Spring Habor Laboratory Press, 363–368 (1991)

    Google Scholar 

  51. Plotnicky-Gilquin, H., et al.: Absence of lung immunopathology following RSV challenge in mice immunized with a recombinant RSV G protein fragment. Virology 258, 128–140 (1999)

    Article  PubMed  CAS  Google Scholar 

  52. Plotnicky-Gilquin, H., et al.: Identification of multiple protective epitopes (protectopes) in the central conserved domain of a prototype human RSV G protein. J. Virol. 73, 5637–5645 (1999)

    PubMed  CAS  Google Scholar 

  53. Plotnicky-Gilquin, H., et al.: CD4(+) T-cell-mediated antiviral protection of the upper respiratory tract in BALB/c mice following parenteral immunization with a recombinant RSV G protein fragment. J. Virol. 74, 3455–3463 (2000)

    Article  PubMed  CAS  Google Scholar 

  54. Plotnicky-Gilquin, H., et al.: Gamma interferon-dependent protection of the mouse upper respiratory tract following parenteral immunization with a RSV G protein fragment. J. Virol. 76, 10203–10210 (2002)

    Article  PubMed  CAS  Google Scholar 

  55. Plotnicky-Gilquin, H., et al.: Passive transfer of serum antibodies induced by BBG2Na, a subunit vaccine, in the elderly protects SCID mouse lungs against RSV challenge. Virology 303, 130–137 (2002)

    Article  PubMed  CAS  Google Scholar 

  56. Plotnicky-Gilquin, H., et al.: Enhanced pulmonary immunopathology following neonatal priming with formalin-inactivated RSV but not with the BBG2NA vaccine candidate. Vaccine 21, 2651–2660 (2003)

    Article  Google Scholar 

  57. Popow-Kraupp, T., Aberle, J.H.: Diagnosis of RSV infection. Open Microbiol. J. 5, 128–134 (2011)

    Article  PubMed  Google Scholar 

  58. Power, U.F., et al.: Induction of protective immunity in rodents by vaccination with a prokaryotically expressed recombinant fusion protein containing a RSV G protein fragment. Virology 230, 155–166 (1997)

    Article  PubMed  CAS  Google Scholar 

  59. Power, U.F., et al.: Identification and characterisation of multiple linear B cell protectopes in the RSV G protein. Vaccine 19, 2345–2351 (2001)

    Article  PubMed  CAS  Google Scholar 

  60. Power, U.F., et al.: Differential histopathology and chemokine gene expression in lung tissues following RSV challenge of formalin-inactivated RSV- or BBG2Na-immunized mice. J. Virol. 75, 12421–12430 (2001)

    Article  PubMed  CAS  Google Scholar 

  61. Power, U.F., et al.: Safety and immunogenicity of a novel recombinant subunit RSV vaccine (BBG2Na) in healthy young adults. J. Infect. Dis. 184, 1456–1460 (2001)

    Article  PubMed  CAS  Google Scholar 

  62. Power, U.F., Plotnicky, H., Blaecke, A., Nguyen, T.N.: The immunogenicity, protective efficacy and safety of BBG2Na, a subunit RSV vaccine candidate, against RSV-B. Vaccine 22, 168–176 (2003)

    Article  PubMed  CAS  Google Scholar 

  63. Prince, G.A., Curtis, S.J., Yim, K.C., Porter, D.D.: Vaccine-enhanced RSV disease in cotton rats following immunization with Lot 100 or a newly prepared reference vaccine. J. Gen. Virol. 82, 2881–2888 (2001)

    PubMed  CAS  Google Scholar 

  64. Siegrist, C.A., et al.: Protective efficacy against RSV following murine neonatal immunization with BBG2Na vaccine: influence of adjuvants and maternal antibodies. J. Infect. Dis. 179, 1326–1333 (1999)

    Article  PubMed  CAS  Google Scholar 

  65. Simard, C., et al.: Subgroup specific protection of mice from RSV infection with peptides encompassing the amino acid region 174–187 from the G glycoprotein: the role of cysteinyl residues in protection. Vaccine 15, 423–432 (1997)

    Article  PubMed  CAS  Google Scholar 

  66. Ståhl, S. et al. In: Pozzi, G., Wells, J. M. (eds.) Gram-Positive Bacteria: Chapter 4: Development of non-pathogenic Staphylococci as vaccine delivery vehicles. Vaccine vehicles for Mucosal Immunization, pp. 62–81. Landes Bioscience, Georgetown (1997)

    Google Scholar 

  67. Tayyari, F., et al.: Identification of nucleolin as a cellular receptor for human RSV. Nat. Med. 17, 1132–1135 (2011)

    Article  PubMed  CAS  Google Scholar 

  68. Tebbey, P.W., Hagen, M., Hancock, G.E.: Atypical pulmonary eosinophilia is mediated by a specific amino acid sequence of the attachment (G) protein of RSV. J. Exp. Med. 188, 1967–1972 (1998)

    Article  PubMed  CAS  Google Scholar 

  69. Tripp, R.A., et al.: CX3C chemokine mimicry by RSV G glycoprotein. Nat. Immunol. 2, 732–738 (2001)

    Article  PubMed  CAS  Google Scholar 

  70. Trudel, M., Nadon, F., Seguin, C., Binz, H.: Protection of BALB/c mice from RSV infection by immunization with a synthetic peptide derived from the G glycoprotein. Virology 185, 749–757 (1991)

    Article  PubMed  CAS  Google Scholar 

  71. Trudel, M., Power, U.F., Stahl, S., Bonnefoy, J.Y., Nguyen,N.T.: Immunogenicity and protective efficacy of a RSV subunit vaccine candidate BBG2Na in African green monkeys. In: 38th ICAAC meeting, San Diego. 24–27 Sept 1998

    Google Scholar 

  72. Varga, S.M., Wissinger, E.L., Braciale, T.J.: The attachment (G) glycoprotein of respiratory syncytial virus contains a single immunodominant epitope that elicits both Th1 and Th2 CD4+ T cell responses. J. Immunol. 165, 6487–6495 (2000)

    PubMed  CAS  Google Scholar 

  73. Walsh, E.E.: RSV infection in adults. Semin. Respir. Crit. Care Med. 32, 423–432 (2011)

    Article  PubMed  Google Scholar 

  74. Yu, J.R., Kim, S., Lee, J.B., Chang, J.: Single intranasal immunization with recombinant adenovirus-based vaccine induces protective immunity against RSV infection. J. Virol. 82, 2350–2357 (2008)

    Article  PubMed  CAS  Google Scholar 

  75. Zeng, R., Zhang, Z., Mei, X., Gong, W., Wei, L.: Protective effect of a RSV subunit vaccine candidate G1F/M2 was enhanced by a HSP70-Like protein in mice. Biochem. Biophys. Res. Commun. 377, 495–499 (2008)

    Article  PubMed  CAS  Google Scholar 

  76. Zhang, W., et al.: Vaccination to induce antibodies blocking the CX3C-CX3CR1 interaction of RSV G protein reduces pulmonary inflammation and virus replication in mice. J. Virol. 84, 1148–1157 (2010)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

C Andersson, M Azin, T Baussant, A Beck, H Binz, JF Boe, JY Bonnefoy, N Bouveret-LeCam, JF Cano, B Chol, JC Corbiere, N Corvaia, N Dagouassat, F Farinole, L Goetsch, M Hansson, JF Haeuw, K Helffer, T Huss, C Issac, C Klinguer, PH Lambert, M Lokteff, S Liljeqvist, M Maitre, C Nadon, Q Nguyen, PA Nygren, H Plotnicky-Gilquin, A Perez, U Power, A Robert, P Samuelsson, CA Siegrist, C Simard, M Trudel, M Uhlén, D Velin and L Zanna.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thien N. Nguyen PhD .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Wien

About this chapter

Cite this chapter

Nguyen, T.N., Libon, C., Ståhl, S. (2013). Subunit Vaccine Candidates Engineered from the Central Conserved Region of the RSV G Protein Aimed for Parenteral or Mucosal Delivery. In: Giese, M. (eds) Molecular Vaccines. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1419-3_5

Download citation

Publish with us

Policies and ethics