Skip to main content

Advertisement

Log in

Combined meningococcal serogroup A and W135 outer-membrane vesicles activate cell-mediated immunity and long-term memory responses against non-covalent capsular polysaccharide A

  • Published:
Immunologic Research Aims and scope Submit manuscript

An Erratum to this article was published on 03 July 2013

Abstract

Outer-membrane vesicles (OMVs) have inherent adjuvant properties, and many vaccines use OMV as vaccine components. Utilizing the adjuvant properties of OMV could lead to the formulation of vaccines that are less expensive and potentially more immunogenic than covalently conjugated polysaccharide vaccines. We evaluated the adjuvant effect in Balb/c mice of combinations of OMV from Neisseria meningitidis serogroup A and W135 as compared to that of the non-covalently conjugated capsular polysaccharide A. Both antigens were adsorbed onto aluminum hydroxide. The mice were given a booster dose of plain polysaccharide A to stimulate an immunologic memory response. Subclasses determination and cytokine assays demonstrated the capacity of OMV to induce a IgG2a/IgG2b isotype profile and IFN-γ production, suggesting the induction of a Th1 pattern immune response. Lymphoproliferative responses to OMVs were high, with affinity maturation of antibodies observed. Bactericidal titers after the booster dose were also observed. Memory B cells and long-term memory T cells were also detected. The results of this study indicate that combined meningococcal serogroup A and W135 OMV can activate cell-mediated immunity and induce a long-term memory response.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Weintraub A. Immunology of bacterial polysaccharide antigens. Carb Res. 2003;338:2539–47.

    Article  CAS  Google Scholar 

  2. Wing J, Smart L, Borrow R, Findlow J, Findlow H, Lees A, Read RC, et al. Correlation of group C meningococcal conjugate vaccine response with B- and T-lymphocyte activity. PLoS ONE. 2012;7:e31160.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Ambrosino DM, Sood SK, Lee MC, Chen D, Collard HR, Bolon DL, Johnson C, et al. IgG1, IgG2 and IgM responses to two Haemophilus influenzae type b conjugate vaccines in young infants. Pediatr Infect Dis J. 1992;11:855–9.

    Article  CAS  PubMed  Google Scholar 

  4. Borrow R, Southern J, Andrews N, Peake N, Rahim R, Acuna M, Martin S, et al. Comparison of antibody kinetics following meningococcal serogroup C conjugate vaccine between healthy adults previously vaccinated with meningococcal A/C polysaccharide vaccine and vaccine-naïve controls. Vaccine. 2001;19:3043–50.

    Article  CAS  PubMed  Google Scholar 

  5. Goldblatt D, Vaz AR, Miller E. Antibody avidity as a surrogate marker of successful priming by Haemophilus influenzae type b conjugate vaccines following infant immunization. J Infect Dis. 1998;177:1112–5.

    Article  CAS  PubMed  Google Scholar 

  6. Gourley TS, Wherry EJ, Masopust D, Ahmed R. Generation and maintenance of immunological memory. Semin Immunol. 2004;16:323–33.

    Article  CAS  PubMed  Google Scholar 

  7. Holst J, Martin D, Arnold R, Campa C, Oster P, O’Hallahan J, Rosenqvist E. Properties and clinical performance of vaccines containing outer membrane vesicles from Neisseria meningitidis. Vaccine. 2009;27S:B3–12.

    Article  Google Scholar 

  8. Sierra G, Campa C, Varcárcel M. Vaccine against group B Neisseria meningitidis: protection trial and mass vaccination results in Cuba. NIPH Annals. 1991;14:195–210.

    CAS  PubMed  Google Scholar 

  9. Pérez O, Mastroeni P, Rodríguez T et al. Proteoliposomes and derivatives thereof as cytotoxic response-inducing adjuvants and resulting formulations EP1716866 A1; 2003.

  10. Pérez O, Bracho G, Lastre M, Sierra G, Campa C, Mora N, del Campo J et al. Método de obtención de estructuras cocleares, Composiciones vacunales y adyuvantes basados en estructuras cocleares y sus intermediarios. Patent application Cu 2002–0292.

  11. Rodríguez T, Pérez O, Ménager N, Ugrinovic S, Bracho G, Mastroeni P. Interactions of proteoliposomes from serogroup B Neisseria meningitidis with bone marrow-derived dendritic cells and macrophages: adjuvant effects and antigen delivery. Vaccine. 2005;23:1312–21.

    Article  PubMed  Google Scholar 

  12. Pérez O, Lastre M, Lapinet J, Bracho G, Díaz M, Zayas C, et al. Immune response induction and new effector mechanisms possibly involved in protection conferred by the Cuban Anti-Meningococcal BC Vaccine. Infect Immun. 2001;2001(6):4502–8.

    Article  Google Scholar 

  13. Pérez O, Lastre M, Lapinet J, Pérez A, Díaz M, Zayas C, et al. Long-lasting cellular immune response in babies, children, and pre-teenagers vaccinated with a proteoliposome based anti-meningococcal BC vaccine. Inmunología. 2001;20:177–83.

    Google Scholar 

  14. Camaraza M, Ochoa R, Arnet A, Sotolongo F, Martínez I, Cuevas I, Hernández D. Inmunogenicidad inducida por la vacuna antimeningocócica VA-MENGOC-BC® contra la cepa de N. meningitidis ATCC C11 en adolescentes después de 12 años de vacunados. Rev Cuba Med Trop. 2004;56:26–30.

    Google Scholar 

  15. Pérez O, Romeu B, Lastre M, Gonzalez E, Balboa J, Zayas C. et al. Adjuvants to polysaccharides vaccines. Patent number 2011 CU-P-2011-2002.

  16. Norheim G, Tunheim G, Næss LM, Kristiansen P, Caugant D, Rosenqvist E. An outer membrane vesicle vaccine for prevention of serogroup A and W-135 meningococcal disease in the African meningitis belt Scand. J Immunol. 2012;76:99–107.

    CAS  Google Scholar 

  17. Campa C, Sierra V, Gutiérrez M, Biset G, García L, Puentes G, Sampedro M. et al. Method of producing Neisseria meningitidis B vaccine, and vaccine produced by method. United States Patent 1997. Patent Number: 5,597,572.

  18. Norheim G, Aase A, Caugant D, Høiby E, Fritzsønn E, Tangen T, Kristiansen P, et al. Development and characterisation of outer membrane vesicle vaccines against serogroup A Neisseria meningitidis. Vaccine. 2005;23:3762–74.

    Article  CAS  PubMed  Google Scholar 

  19. Romeu B, González E, Zayas C, Del Campo J, Acevedo R, Cuello M, Valdes Y, et al. AFCo1 as nasal adjuvant of capsular polysaccharide from Neisseria meningitidis serogroup C induces systemic and mucosal immune responses. Scand J Infect Dis. 2011;43:809–13.

    Article  CAS  PubMed  Google Scholar 

  20. Anttila M, Eskola J, Ahman H, Kayht H. Avidity of IgG for Streptococcus pneumoniae Type 6B and 23F Polysaccharides in Infants Primed with Pneumococcal Conjugates and Boosted with Polysaccharide or Conjugate Vaccines J. Infect Dis. 1998;177:1614–21.

    Article  CAS  Google Scholar 

  21. Norheim G, Arne Høiby E, Caugant DA, Namork E, Tangen T, Fritzsønn E, Rosenqvist E. Immunogenicity and bactericidal activity in mice of an outer membrane protein vesicle vaccine against Neisseria meningitidis serogroup A disease. Vaccine. 2004;22:2171–80.

    Article  CAS  PubMed  Google Scholar 

  22. Mata E, Igartua M, Patarroyo ME, Pedraz JL, Hernández R. Enhancing immunogenicity to PLGA microparticulate systems by incorporation of alginate and RGD-modified alginate Eur. J Pharm Sci. 2011;44:32–40.

    CAS  Google Scholar 

  23. Carcaboso AM, Hernandez RM, Igartua M, Rosas JE, Patarroyo ME, Pedraz JL. Potent, long lasting systemic antibody levels and mixed Th1/Th2 immune response after nasal immunization with malaria antigen loaded PLGA microparticles. Vaccine. 2004;22:1423–32.

    Article  CAS  PubMed  Google Scholar 

  24. Hennekena M, Burdinb N, Thoroddsenc E, Sigurdardottir S, Trannoyb E, Jonsdottir I. Meningococcal serogroup C polysaccharide specific memory B cells, directly enumerated by labeled polysaccharide, are not affected by age at vaccination. Vaccine. 2010;28:2097–103.

    Article  Google Scholar 

  25. Keating SM, Bejon P, Berthoud T, Vuola J, Todryk S, Webster D, Dunachie S, et al. Durable human memory T cells quantifiable by cultured enzyme-linked immunospot assays are induced by heterologous prime boost immunization and correlate with protection against malaria. J Immunol. 2005;175:5675–80.

    Article  CAS  PubMed  Google Scholar 

  26. Trotter C, McVernon J, Ramsay M, Whitney C, Mulholland E, Goldblatt D, Hombach J, et al. Optimising the use of conjugate vaccines to prevent disease caused by Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae. Vaccine. 2008;26:4434–45.

    Article  CAS  PubMed  Google Scholar 

  27. Pollard AJ, Perrett KP, Beverley PC. Maintaining protection against invasive bacteria with protein polysaccharide conjugate vaccines. Nat Rev Immunol. 2009;9:213–20.

    Article  CAS  PubMed  Google Scholar 

  28. Granoff D, Pollard A. Reconsideration of the use of meningococcal polysaccharide vaccine. Ped Infect Dis J. 2007;26:716–22.

    Article  Google Scholar 

  29. Pérez O, Bracho G, Lastre M, Mora N, del Campo J, Gil D, Zayas C, et al. Novel adjuvant based on a proteoliposome-derived cochleate structure containing native lipopolysaccharide as a pathogen associated molecular pattern. Immunol Cell Biol. 2004;82:603–10.

    Article  PubMed  Google Scholar 

  30. Poolman J, Borrow R. Hyporesponsiveness and its clinical implications after vaccination with polysaccharide or glycoconjugate vaccines. Expert Rev Vaccines. 2011;10:307–22.

    Article  CAS  PubMed  Google Scholar 

  31. Joseph H, Ryall R, Bybel M, Papa T, MacLennan J, Buttery J, Borrow R. Immunogenicity and immunological priming of the serogroup A portion of a bivalent meningococcal A/C conjugate vaccine in 2-year-old children. J Infect Dis. 2003;187:1142–6.

    Article  CAS  PubMed  Google Scholar 

  32. Reingold AL, Broome CV, Hightower A, Ajello G, Bolan G, Adamsbaum C, Jones E, et al. Age-specific differences in duration of clinical protection after vaccination with meningococcal polysaccharide A vaccine. Lancet. 1985;326:114–8.

    Article  Google Scholar 

  33. Ismail AA, Harris SL, Granoff DM. Serum group A anticapsular antibodies in a Sudanese population immunized with meningococcal polysaccharide vaccine during a group A epidemic. Pediatr Infect Dis J. 2004;23:748–55.

    Article  PubMed  Google Scholar 

  34. Lambert PH, Liu M, Siegrist CA. Can successful vaccines teach us how to induce efficient protective immune responses? Nat Med. 2005;11:S54–62.

    Article  CAS  PubMed  Google Scholar 

  35. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–89.

    Article  CAS  PubMed  Google Scholar 

  36. Taillardet M, Haffar G, Mondie P, Asensio MJ, Pleau-Pison T, Burdin N, Defrance T, et al. Toll-like receptor agonists allow generation of long-lasting Antipneumococcal humoral immunity in response to a plain Polysaccharidic Vaccine. J Infect Dis. 2010;202:470–9.

    Article  CAS  PubMed  Google Scholar 

  37. Gourley T, Wherry EJ, Masopust D, Ahmed R. Generation and maintenance of immunological memory. Semin Immunol. 2004;16:323–33.

    Article  CAS  PubMed  Google Scholar 

  38. Heyzer-Williams LJ, Heyzer-Williams MG. Antigen-specific memory B cell development. Ann Rev Immunol. 2005;23:487–513.

    Article  Google Scholar 

  39. Deauvieau F, Dussurgey S, Rossignol D, de Montfort A, Burdin N, Guy B. Memory B and T cell responses induced by serotype 4 Streptococcus pneumonia vaccines: longitudinal analysis comparing responses elicited by free polysaccharide, conjugate and carrier. Vaccine. 2010;28:576–82.

    Article  Google Scholar 

  40. Obukhanych TV, Nussenzweig MC. T-independent type II immune responses generate memory B cells. J Exp Med. 2006;203:305–10.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Clarke ET, Williams NA, Dull PM, Findlow J, Borrow R, Finn A, Heyderman RS. Polysaccharide–protein conjugate vaccination induces antibody production but not sustained B-cell memory in the human nasopharyngeal mucosa. Mucosal Immunol. 2013;6:288–96.

    Article  CAS  PubMed  Google Scholar 

  42. Saunders NB, Shoemaker DR, Brandt BL, Moran EE, Larsen T, Zollinger WD. Immunogenicity of intranasally administered meningococcal native outer membrane vesicles in mice. Infect Immun. 1999;67:113–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Campo JD, Zayas C, Romeu B, Acevedo R, González E, Bracho G, Cuello M, Cabrera O, Balboa J, Lastre M. Mucosal immunization using proteoliposome and cochleate structures from Neisseria meningitidis serogroup B induce mucosal and systemic responses. Methods. 2009;49:301–8.

    Article  PubMed  Google Scholar 

  44. Avci F, Kasper DL. How bacterial carbohydrates influence the adaptive immune system. Ann Rev Immunol. 2010;28:107–30.

    Article  CAS  Google Scholar 

  45. Butler NS, Nolz JC, Harty JT. Immunologic considerations for generating memory CD8 T cells through vaccination Cell. Microbiol. 2011;13:925–33.

    CAS  Google Scholar 

  46. Avci F, Li X, Tsuji M, Kasper D. A mechanism for glycoconjugate vaccine activation of the adaptive immune system and its implications for vaccine design. Nature Med. 2011;17:1602–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Finlay Institute for the support and sponsorship of this work. We gratefully acknowledge the help of Professor Nelson Fernández from University of Essex, UK, for reading the manuscript. We also thank Laura Reyes, Yusnaby Borrero, and Diandra Lescaille for their excellent technical assistance. We thank Dr. Daniel Cardoso, Vice president of Finlay Institute, and Dr. Reinaldo Acevedo for supporting this work. Also, we would like to thank the NFR GLOBVAC project “Development of an outer membrane vesicle vaccine for Africa, against serogroup A and W135 meningococcal disease” Project number: 192477 and Dr. Einar Rosenqvist, Dr Gunnstein Norheim, Dr. Lisbeth Naess, and Dr. Gro Turheim from Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway, for supporting the OMV from serogroup A and W135 production and characterization.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Belkis Romeu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Romeu, B., Lastre, M., García, L. et al. Combined meningococcal serogroup A and W135 outer-membrane vesicles activate cell-mediated immunity and long-term memory responses against non-covalent capsular polysaccharide A. Immunol Res 58, 75–85 (2014). https://doi.org/10.1007/s12026-013-8427-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-013-8427-6

Keywords

Navigation