Advertisement

Glycoconjugate Journal

, Volume 27, Issue 7–9, pp 643–648 | Cite as

Investigating the candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: immunology of glycoconjugates with high carbohydrate loading

  • Andrew D. Cox
  • Frank St. Michael
  • Dhamodharan Neelamegan
  • Suzanne Lacelle
  • Chantelle M. Cairns
  • Marzia M. Giuliani
  • Alessia Biolchi
  • J. Claire Hoe
  • E. Richard Moxon
  • James C. Richards
Article

Abstract

We investigated the immune responses of rabbits that were immunised with lipopolysaccharide (LPS)-based glycoconjugates by measuring the reactivity of the derived sera to a panel of selected wild-type and mutant strains of Neisseria meningitidis. In all cases, high titers of antibodies capable of recognising LPS elaborating the identical structure as presented on the immunising glycoconjugate were obtained, and in most cases the derived sera also recognised heterologous strains including wild-type, but at lower titers. However, although serum bactericidal antibodies were consistently obtained against strains elaborating the same LPS structure as the immunising antigen, this functional response was not observed against wild-type strains. We identified several potentially competing neo-epitopes that had been introduced via our conjugation strategies, which might compete with the conserved inner core oligosaccharide target region, thus reducing the antibody titers to epitopes which could facilitate bactericidal killing. This study has therefore identified key factors that are crucial to control in order to increase the likelihood of obtaining bactericidal antibodies to wild-type meningococcal cells with LPS-derived glycoconjugates. Glycoconjugates utilised in this study, have been found to contain epitopes that do not contribute to the derivation of antibodies that may facilitate bactericidal killing of wild-type strains and must be avoided in future LPS-based glycoconjugate preparations.

Keywords

Neisseria meningitidis Conjugate vaccine LPS 

Notes

Acknowledgements

We thank Perry Fleming (core Bacterial Culture Facility) for large scale biomass production, Jacek Stupak for recording CE-ES-MS and the NRC-IBS animal facility for animal care. This work was supported by Novartis Vaccines. We thank Drs. Paolo Costantino and Francesco Berti for helpful discussions.

References

  1. 1.
    Plested, J.S., Makepeace, K., Jennings, M.P., Gidney, M.A., Lacelle, S., Brisson, J.R., Cox, A.D., et al.: Conservation and accessibility of an inner core lipopolysaccharide epitope of Neisseria meningitidis. Infect. Immun. 67, 5417–5426 (1999)PubMedGoogle Scholar
  2. 2.
    Gidney, M.A.J., Plested, J.S., Lacelle, S., Coull, P.A., Wright, J.C., Makepeace, K., et al.: Development, characterisation and functional activity of a panel of specific monoclonal antibodies to inner core lipopolysaccharide (LPS) epitopes in Neisseria meningitidis. Infect. Immun. 72, 559–569 (2004)CrossRefPubMedGoogle Scholar
  3. 3.
    Plested, J.S., Harris, S.L., Wright, J.C., Coull, P.A., Makepeace, K., Gidney, M.A.J., et al.: Highly conserved Neisseria meningitidis inner-core lipopolysaccharide epitope confers protection against experimental meningococcal bacteremia. J. Infect. Dis. 187, 1223–1234 (2003)CrossRefPubMedGoogle Scholar
  4. 4.
    Cox, A.D., Zou, W., Gidney, M.A.J., Lacelle, S., Plested, J.S., Makepeace, K., et al.: Candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: developmental chemistry and investigation of immunological responses following immunization of mice and rabbits. Vaccine 23, 5045–5054 (2005)CrossRefPubMedGoogle Scholar
  5. 5.
    Cox, A.D., St. Michael, F., Neelamegan, D., Lacelle, S., Cairns, C.M., Richards, J.C.: Investigating the candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: chemical strategies to prepare glycoconjugates with good carbohydrate loading. Glycoconjugate J. 27, 401–417 (2010)CrossRefGoogle Scholar
  6. 6.
    Giuliani, M.M., Santini, L., Brunelli, B., Biolchi, A., Arico, B., Di Marcello, F., et al.: The region comprising amino acids 100 to 255 of Neisseria meningitidis lipoprotein GNA 1870 elicits bactericidal antibodies. Infect. Immun. 73, 1151–1160 (2005)CrossRefPubMedGoogle Scholar
  7. 7.
    Masoud, H., Perry, M.B., Brisson, J.-R., Uhrin, D., Richards, J.C.: Structural elucidation of the backbone oligosaccharide from the lipopolysaccharide of Moraxella catarrhalis serotype A. Can. J. Chem. 72, 1466–1477 (1994)CrossRefGoogle Scholar
  8. 8.
    Edebrink, P., Jansson, P.-E., Widmalm, G., Holme, T., Rahman, M.: The structures of oligosaccharides isolated from the lipopolysaccharide of Moraxella catarrhalis serotype B, strain CCUG 3292. Carbohydr. Res. 295, 127–146 (1996)PubMedGoogle Scholar
  9. 9.
    Edebrink, P., Jansson, P.-E., Rahman, M.M., Widmalm, G., Holme, T., Rahman, M.: Structural studies on the O-antigen oligosaccharides from two strains of Moraxella catarrhalis serotype C. Carbohydr. Res. 266, 237–261 (1995)CrossRefPubMedGoogle Scholar
  10. 10.
    Bartoloni, A., Norelli, F., Ceccarini, C., Rappuoli, R., Costantino, P.: Immunogenicity of meningococcal B polysaccharide conjugated to tetanus toxoid or CRM197 via adipic acid dihydrazide. Vaccine 13, 463–470 (1995)CrossRefPubMedGoogle Scholar
  11. 11.
    Peeters, J.M., Hazendonk, T.G., Beuvery, E.C., Tesser, G.I.: Comparison of four bifunctional reagents for coupling peptides to proteins and the effect of the three moieties on the immunogenicity of the conjugates. J. Immunol. Methods 120, 133–143 (1989)CrossRefPubMedGoogle Scholar
  12. 12.
    Verez-Bencomo, V., Fernández-Santana, V., Hardy, E., Toledo, M.E., Rodríguez, M.C., Heynngnezz, L., et al.: A synthetic conjugate polysaccharide vaccine against Haemophilus influenzae type B. Science 305, 522–525 (2004)CrossRefPubMedGoogle Scholar
  13. 13.
    Torano, G., Toledo, M.E., Baly, A., Fernandez-Santana, V., Rodriguez, F., Alvarez, Y., et al.: Phase I clinical evaluation of a synthetic oligosaccharide-protein conjugate vaccine against Haemophilus influenzae type B in human adult volunteers. Clin. Vaccine. Immunol. 13, 1052–1056 (2006)CrossRefPubMedGoogle Scholar

Copyright information

© Her Majesty the Queen in Right of Canada 2010

Authors and Affiliations

  • Andrew D. Cox
    • 1
  • Frank St. Michael
    • 1
  • Dhamodharan Neelamegan
    • 1
  • Suzanne Lacelle
    • 1
  • Chantelle M. Cairns
    • 1
  • Marzia M. Giuliani
    • 2
  • Alessia Biolchi
    • 2
  • J. Claire Hoe
    • 3
  • E. Richard Moxon
    • 3
  • James C. Richards
    • 1
  1. 1.Institute for Biological Sciences, National Research CouncilOttawaCanada
  2. 2.Novartis VaccinesSienaItaly
  3. 3.Weatherall Institute for Molecular MedicineUniversity of OxfordOxonUK

Personalised recommendations