The Development of Genetically Defined Live Bacterial Vaccines

  • Steven Chatfield
  • Neil Fairweather
  • John Tite
  • Ian Charles
  • Mark Roberts
  • Mario Posada
  • Richard Strugnell
  • Gordon Dougan
Part of the Federation of European Microbiological Societies Symposium Series book series (FEMS, volume 58)


It has long been recognised that vaccination with live organisms can induce more effective protection against infectious diseases than the use of dead vaccines presented in conjunction with currently available adjuvants. Live vaccines offer particular advantages in their ability to induce cell-mediated immune responses which are often critical for the establishment of solid protection against certain infectious agents. The route of vaccine delivery is also of importance. Oral vaccines can induce immune responses at mucosal surfaces and such responses are often lacking in individuals who receive parenteral vaccines. The combination of live organisms with oral delivery thus offers potential advantages for creating practical and efficacious vaccines. Many problems were experienced with early live vaccines because of the frequent occurrence of reversion to virulence and batch to batch variation. These problems were difficult to deal with because the attenuating lesions present in avirulent vaccine strains derived from virulent pathogens were uncharacterised at the genetic level. Recent advances in our understanding of the genetics and the mechanisms employed by pathogens to establish infections in the host has allowed the construction of genetically defined attenuated derivatives of many pathogens.


Vaccine Strain Live Vaccine Yersinia Enterocolitica Bordetella Pertussis Tetanus Toxin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Black, W. J. and S. Falkow. 1987. Construction and characterisation of Bordetella pertussis toxin mutants. Infect. Immun. 55: 2465–2470.Google Scholar
  2. 2.
    Bowe, F., P. O’Gaora, D. Maskell, M. Cafferkey, and G. Dougan. 1989. Virulence, persistence, and immunogenicity of Yersinia enterocolitica 0:8 aroA mutants. Infect. Immun. 57: 3234–3236.PubMedGoogle Scholar
  3. 3.
    Brown, A., C. E. Hormaeche, R. DeMarco de Hormaeche, M. D. Winther, G. Dougan, D. J. Maskell, and B. A. D. Stocker. 1987. An attenuated aroAS.typhimurium vaccine elicits humoral and cellular immunity to cloned beta-galactosidase in mice. J. Infect. Dis. 155: 86–92.PubMedCrossRefGoogle Scholar
  4. 4.
    O’Callaghan, D., D. Maskell, F. Y. Liew, C. S. F. Easmon, and G. Dougan. 1988. Characterisation of aromatic and purine-dependent Salmonella typhimurium: attenuation, persistence, and ability to induce protective immunity in BALB/c mice. Infect. Immun. 56: 419–423.PubMedGoogle Scholar
  5. 5.
    Chatfield, S. N., R. A. Strugnell, and G. Dougan. 1989. Live Salmonella as vaccines and carriers of foreign antigenic determinants. Vaccine 7: 495–498.PubMedCrossRefGoogle Scholar
  6. 6.
    Collins, F. M. 1974. Vaccines and cell-mediated immunity. Bacteriol. Rev., 38: 371–389.PubMedGoogle Scholar
  7. 7.
    Curtiss III, R. and S. M. Kelly. 1987. Salmonella typhimurium deletion mutants lacking adenylate cyclase and cyclic AMP receptor protein are avirulent and immunogenic. Infect. Immun. 55: 3035–3043.PubMedGoogle Scholar
  8. 8.
    Dorman, C. J., S. Chatfield, C. F. Higgins, C. Hayward, and G. Dougan. 1989. Characterization of porin and ompR mutants of a virulent strain of Salmonella typhimurium: ompR mutants are attenuated in vivo. Infect. Immun. 57: 2136–2140.PubMedGoogle Scholar
  9. 9.
    Dougan, G., D. Maskell, D. Pickard, and C. Hormaeche. 1987. Isolation of stable aroA mutants of Salmonella typhi Ty2: properties and preliminary characterisation in mice. Mol. Gen. Genet. 207: 402–405.PubMedCrossRefGoogle Scholar
  10. 10.
    Dougan, G., S. Chatfield, D. Pickard, J. Bester, D. O’Callaghan, and D. Maskell. 1988. Construction and characterization of Salmonella vaccine strains harbouring mutations in two different aro genes. J. Infect. Dis. 158: 1329–1335.PubMedCrossRefGoogle Scholar
  11. 11.
    Fairweather, N. F., S. N. Chatfield, A. J. Makoff, R. A. Strugnell, J. Bester, D. J. Maskell and G. Dougan. 1990. Oral vaccination of mice against tetanus by use of a live attenuated Salmonella carrier. Infect. Immun. 58: 1323–1326.PubMedGoogle Scholar
  12. 12.
    Fields, P. I., E. A. Groisman and F. Heffron. 1989. A Salmonella locus that controls resistance to microbicidal proteins from phagocytic cells. Science 243: 1059–1061.PubMedCrossRefGoogle Scholar
  13. 13.
    Hoiseth, S. K. and B. A. D. Stocker. 1981. Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature (London) 291: 238–239.CrossRefGoogle Scholar
  14. 14.
    Hone, D., R. Morona, S. Attridge and J. Hackett. 1987. Construction of defined galE mutants of Salmonella for use as vaccines. J. Infect. Dis. 156: 167–173PubMedCrossRefGoogle Scholar
  15. 15.
    Jones, P. W., G. Dougan, C. Hayward, N. Mackensie, P. Collins and S. N. Chatfield. 1990. Oral vaccination of calves against experimental Salmonellosis using a double aro mutant of Salmonella typhimurium. Vaccine (in press).Google Scholar
  16. 16.
    Kaper, J. B., H. Lockman, M. M. Baldini, and M. M. Levine. 1984. Recombinant non-toxinogenic Vibrio cholerae strains as attenuated cholera vaccine candidates. Nature (London) 308: 655–658.CrossRefGoogle Scholar
  17. 17.
    McFarland, W. C. and B. A. D. Stocker. 1987. Effect of different purine auxotrophic mutations on mouse virulence of a Vi-positive strain of Salmonella dublin and of two strains of Salmonella typhimurium. Microbiol. Path. 3: 129–141.CrossRefGoogle Scholar
  18. 18.
    Mekalanos, J. J., D. J. Swartz, G. D. N. Pearson, N. Harford, F. Groyne, and M. De Wilde. 1983. Cholera toxin genes: nucleotide sequence, deletion analysis and vaccine development. Nature 306: 551–556.PubMedCrossRefGoogle Scholar
  19. 19.
    Miller, I. A., S. Chatfield, G. Dougan, L. De Silva, H. S. Joysey, and C. E. Hormaeche. 1989. Bacteriophage P22 as a vehicle for transducing cosmid gene banks between smooth strains of Salmonella typhimurium: use in identifying a role for aroD in attenuating virulent Salmonella strains. Mol. Gen. Genet. 215: 312–316.PubMedCrossRefGoogle Scholar
  20. 20.
    Miller, V. I., and J. J. Mekalanos. 1988. Novel suicide vector and its use in construction of insertion mutations: osmoregulation of outer membrane proteins and virulence determinants in Vibrio cholerae requires toxR. J. Bacteriol. 170: 2575–2579.PubMedGoogle Scholar
  21. 21.
    Roberts, M., D. Maskell, P. Novotny, and G. Dougan. 1990. Construction and characterization in vivo of Bordetella pertussis aroA Mutants. Infect. Immun. 58; 732–739.PubMedGoogle Scholar
  22. 22.
    Stocker, B. A. D. 1988. Auxotrophic Salmonella typhi as live vaccine. Vaccine 6: 141–145.PubMedCrossRefGoogle Scholar
  23. 23.
    Strugnell, R. A., D. Maskell, N. Fairweather, D. Pickard, A. Cockayne, C. Penn, and G. Dougan. 1990. Stable expression of foreign antigens from the chromosome of Salmonella typhimurium vaccine strains. Gene 88: 57–63.PubMedCrossRefGoogle Scholar
  24. 24.
    Tite, J. P., X-M. Gao, C. M. Hughes-Jenkins, M. Lipscombe, D. O’Callaghan, G. Dougan, and F. Y. Liew. 1990. Anti-viral immunity induced by recombinant nucleoprotein of influenza A virus. III. Delivery of recombinant nucleoprotein to the immune system using attenuated Salmonella typhimurium as a live carrier. Immunology, 70: (540–546)PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Steven Chatfield
    • 1
  • Neil Fairweather
    • 1
  • John Tite
    • 1
  • Ian Charles
    • 1
  • Mark Roberts
    • 1
  • Mario Posada
    • 1
  • Richard Strugnell
    • 1
  • Gordon Dougan
    • 1
  1. 1.Department of Molecular BiologyWellcome BiotechBeckenham KentUK

Personalised recommendations