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. 1997 Mar;65(3):1053–1060. doi: 10.1128/iai.65.3.1053-1060.1997

Bactericidal antibody responses of juvenile rhesus monkeys immunized with group B Neisseria meningitidis capsular polysaccharide-protein conjugate vaccines.

W D Zollinger 1, E E Moran 1, S J Devi 1, C E Frasch 1
PMCID: PMC175087  PMID: 9038315

Abstract

Reports on the bactericidal activities of antibodies to group B Neisseria meningitidis capsular polysaccharide (B PS) are conflicting. Using three different complement sources, we analyzed the bactericidal activities of sera of juvenile rhesus monkeys immunized with five conjugate vaccines of B PS synthesized by different schemes, an Escherichia coli K92 conjugate, and a noncovalent complex of B PS with group B meningococcal outer membrane vesicles (B+OMV) (S. J. N. Devi, W. D. Zollinger, P. J. Snoy, J. Y. Tai, P. Costantini, F. Norelli, R. Rappuoli, and C. E. Frasch, Infect. Immun. 65:1045-1052, 1997). With rabbit complement, nearly all preimmune sera showed relatively high bactericidal titers, and all vaccines, except the K92 conjugate, induced a fourfold or greater increase in bactericidal titers in most of the monkeys vaccinated. In contrast, with human complement, most prevaccination sera showed no bactericidal activity and in most of the vaccine groups, little or no increase in bactericidal titer was observed. However, the covalent conjugation of P BS and OMV (B-OMV) administered with and without the Ribi adjuvant induced relatively high bactericidal titers which persisted up to 30 weeks. An analysis of the specificities of bactericidal antibodies revealed that absorption with E. coli K1 cells did not change the bactericidal titer with human complement but reduced the titers observed with the rabbit and monkey complements. A significant increase in anti-lipopolysaccharide (LPS) antibodies was elicited by the B-OMV conjugates, and nearly all of the bactericidal activity with human complement could be inhibited with the purified group B meningococcal L3,7,8 LPS. B-OMV covalently coupled via adipic acid dihydrazide elicited significantly elevated levels (P < or = 0.02) of anti-OMV antibodies compared to those of the noncovalently complexed B+OMV. An initial small-scale evaluation of B PS conjugates in adult human males appears feasible, with careful monitoring, to settle the inconsistent reports of the importance of source of complement in eliciting bacteriolysis. Subsequent analysis of resultant human antibodies for bacteriolysis, opsonophagocytosis, and protective efficacy in animal models may be the first step toward answering safety- and efficacy-related concerns about B PS conjugate vaccines.

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Selected References

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  1. Amir J., Liang X., Granoff D. M. Variability in the functional activity of vaccine-induced antibody to Haemophilus influenzae type b. Pediatr Res. 1990 Apr;27(4 Pt 1):358–364. doi: 10.1203/00006450-199004000-00008. [DOI] [PubMed] [Google Scholar]
  2. Amir J., Scott M. G., Nahm M. H., Granoff D. M. Bactericidal and opsonic activity of IgG1 and IgG2 anticapsular antibodies to Haemophilus influenzae type b. J Infect Dis. 1990 Jul;162(1):163–171. doi: 10.1093/infdis/162.1.163. [DOI] [PubMed] [Google Scholar]
  3. Azmi F. H., Lucas A. H., Spiegelberg H. L., Granoff D. M. Human immunoglobulin M paraproteins cross-reactive with Neisseria meningitidis group B polysaccharide and fetal brain. Infect Immun. 1995 May;63(5):1906–1913. doi: 10.1128/iai.63.5.1906-1913.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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. 1995 Apr;13(5):463–470. doi: 10.1016/0264-410x(94)00007-a. [DOI] [PubMed] [Google Scholar]
  5. Devi S. J., Hayat U., Frasch C. E., Kreger A. S., Morris J. G., Jr Capsular polysaccharide-protein conjugate vaccines of carbotype 1 Vibrio vulnificus: construction, immunogenicity, and protective efficacy in a murine model. Infect Immun. 1995 Aug;63(8):2906–2911. doi: 10.1128/iai.63.8.2906-2911.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Devi S. J., Karpas A. B., Frasch C. E. Binding diversity of monoclonal antibodies to alpha(2-->8) polysialic acid conjugated to outer membrane vesicle via adipic acid dihydrazide. FEMS Immunol Med Microbiol. 1996 Jul;14(4):211–220. doi: 10.1111/j.1574-695X.1996.tb00289.x. [DOI] [PubMed] [Google Scholar]
  7. Devi S. J., Robbins J. B., Schneerson R. Antibodies to poly[(2----8)-alpha-N-acetylneuraminic acid] and poly[(2----9)-alpha-N-acetylneuraminic acid] are elicited by immunization of mice with Escherichia coli K92 conjugates: potential vaccines for groups B and C meningococci and E. coli K1. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7175–7179. doi: 10.1073/pnas.88.16.7175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Devi S. J., Zollinger W. D., Snoy P. J., Tai J. Y., Costantini P., Norelli F., Rappuoli R., Frasch C. E. Preclinical evaluation of group B Neisseria meningitidis and Escherichia coli K92 capsular polysaccharide-protein conjugate vaccines in juvenile rhesus monkeys. Infect Immun. 1997 Mar;65(3):1045–1052. doi: 10.1128/iai.65.3.1045-1052.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ey P. L., Russell-Jones G. J., Jenkin C. R. Isotypes of mouse IgG--I. Evidence for 'non-complement-fixing' IgG1 antibodies and characterization of their capacity to interfere with IgG2 sensitization of target red blood cells for lysis by complement. Mol Immunol. 1980 Jun;17(6):699–710. doi: 10.1016/0161-5890(80)90139-x. [DOI] [PubMed] [Google Scholar]
  10. Goldschneider I., Gotschlich E. C., Artenstein M. S. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med. 1969 Jun 1;129(6):1307–1326. doi: 10.1084/jem.129.6.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Griffiss J. M., Goroff D. K. IgA blocks IgM and IgG-initiated immune lysis by separate molecular mechanisms. J Immunol. 1983 Jun;130(6):2882–2885. [PubMed] [Google Scholar]
  12. Jennings H. J., Gamian A., Michon F., Ashton F. E. Unique intermolecular bactericidal epitope involving the homosialopolysaccharide capsule on the cell surface of group B Neisseria meningitidis and Escherichia coli K1. J Immunol. 1989 May 15;142(10):3585–3591. [PubMed] [Google Scholar]
  13. Jennings H. J., Lugowski C., Ashton F. E. Conjugation of meningococcal lipopolysaccharide R-type oligosaccharides to tetanus toxoid as route to a potential vaccine against group B Neisseria meningitidis. Infect Immun. 1984 Jan;43(1):407–412. doi: 10.1128/iai.43.1.407-412.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jennings H. J., Roy R., Gamian A. Induction of meningococcal group B polysaccharide-specific IgG antibodies in mice by using an N-propionylated B polysaccharide-tetanus toxoid conjugate vaccine. J Immunol. 1986 Sep 1;137(5):1708–1713. [PubMed] [Google Scholar]
  15. Kasper D. L., Winkelhake J. L., Zollinger W. D., Brandt B. L., Artenstein M. S. Immunochemical similarity between polysaccharide antigens of Escherichia coli 07: K1(L):NM and group B Neisseria meningitidis. J Immunol. 1973 Jan;110(1):262–268. [PubMed] [Google Scholar]
  16. Lifely M. R., Esdaile J. Specificity of the immune response to the group B polysaccharide of Neisseria meningitidis. Immunology. 1991 Nov;74(3):490–496. [PMC free article] [PubMed] [Google Scholar]
  17. Lifely M. R., Moreno C., Lindon J. C. An integrated molecular and immunological approach towards a meningococcal group B vaccine. Vaccine. 1987 Mar;5(1):11–26. doi: 10.1016/0264-410x(87)90004-1. [DOI] [PubMed] [Google Scholar]
  18. Lifely M. R., Roberts S. C., Shepherd W. M., Esdaile J., Wang Z., Cleverly A., Aulaqi A. A., Moreno C. Immunogenicity in adult males of a Neisseria meningitidis group B vaccine composed of polysaccharide complexed with outer membrane proteins. Vaccine. 1991 Jan;9(1):60–66. doi: 10.1016/0264-410x(91)90318-z. [DOI] [PubMed] [Google Scholar]
  19. Mandrell R. E., Azmi F. H., Granoff D. M. Complement-mediated bactericidal activity of human antibodies to poly alpha 2-->8 N-acetylneuraminic acid, the capsular polysaccharide of Neisseria meningitidis serogroup B. J Infect Dis. 1995 Nov;172(5):1279–1289. doi: 10.1093/infdis/172.5.1279. [DOI] [PubMed] [Google Scholar]
  20. Moran E. E., Brandt B. L., Zollinger W. D. Expression of the L8 lipopolysaccharide determinant increases the sensitivity of Neisseria meningitidis to serum bactericidal activity. Infect Immun. 1994 Dec;62(12):5290–5295. doi: 10.1128/iai.62.12.5290-5295.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Raff H. V., Devereux D., Shuford W., Abbott-Brown D., Maloney G. Human monoclonal antibody with protective activity for Escherichia coli K1 and Neisseria meningitidis group B infections. J Infect Dis. 1988 Jan;157(1):118–126. doi: 10.1093/infdis/157.1.118. [DOI] [PubMed] [Google Scholar]
  22. Rosenqvist E., Høiby E. A., Wedege E., Bryn K., Kolberg J., Klem A., Rønnild E., Bjune G., Nøkleby H. Human antibody responses to meningococcal outer membrane antigens after three doses of the Norwegian group B meningococcal vaccine. Infect Immun. 1995 Dec;63(12):4642–4652. doi: 10.1128/iai.63.12.4642-4652.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ross S. C., Rosenthal P. J., Berberich H. M., Densen P. Killing of Neisseria meningitidis by human neutrophils: implications for normal and complement-deficient individuals. J Infect Dis. 1987 Jun;155(6):1266–1275. doi: 10.1093/infdis/155.6.1266. [DOI] [PubMed] [Google Scholar]
  24. Schlesinger Y., Granoff D. M. Avidity and bactericidal activity of antibody elicited by different Haemophilus influenzae type b conjugate vaccines. The Vaccine Study Group. JAMA. 1992 Mar 18;267(11):1489–1494. [PubMed] [Google Scholar]
  25. Verheul A. F., Van Gaans J. A., Wiertz E. J., Snippe H., Verhoef J., Poolman J. T. Meningococcal lipopolysaccharide (LPS)-derived oligosaccharide-protein conjugates evoke outer membrane protein- but not LPS-specific bactericidal antibodies in mice: influence of adjuvants. Infect Immun. 1993 Jan;61(1):187–196. doi: 10.1128/iai.61.1.187-196.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Zollinger W. D., Boslego J. E., Frasch C. E., Froholm L. O. Safety of vaccines containing meningococcal group B polysaccharide. Lancet. 1984 Jul 21;2(8395):166–166. doi: 10.1016/s0140-6736(84)91083-3. [DOI] [PubMed] [Google Scholar]
  27. Zollinger W. D., Mandrell R. E., Griffiss J. M., Altieri P., Berman S. Complex of meningococcal group B polysaccharide and type 2 outer membrane protein immunogenic in man. J Clin Invest. 1979 May;63(5):836–848. doi: 10.1172/JCI109383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Zollinger W. D., Mandrell R. E. Importance of complement source in bactericidal activity of human antibody and murine monoclonal antibody to meningococcal group B polysaccharide. Infect Immun. 1983 Apr;40(1):257–264. doi: 10.1128/iai.40.1.257-264.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Zollinger W. D., Moran E. Meningococcal vaccines--present and future. Trans R Soc Trop Med Hyg. 1991;85 (Suppl 1):37–43. doi: 10.1016/0035-9203(91)90339-z. [DOI] [PubMed] [Google Scholar]

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