Oral Delivery of Antigens in Live Bacterial Vectors

  • Robert N. Brey
  • Garvin S. Bixler
  • James P. Fulginiti
  • Deborah A. Dilts
  • Marta I. J. Sabara
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 303)


Most available vaccines for enteric diseases are cinactivated whole cell preparations which provide incomplete cprotection against infection and have undesirable side effects. cAs alternative vaccines for enteric infection, several live oral cvaccines have been recently developed. These vaccines are cderived from virulent pathogens by introduction of stable cattenuating mutations in metabolic pathway genes. Ideally, cthese mutations are non-reverting and genetically well defined. cThe Salmonella typhi live oral vaccine Ty21a has been tested in cseveral field trials, first in Egypt and more recently in four cseparate trials in Chilean schoolchildren (Ferreccio et al, 1989; Levine et al 1987a; Wahdan et al, 1982). The results of cthose trials indicate that Ty21a is safe, well tolerated, and cprovides 66% protection in a typhoid fever endemic area. cProtection against typhoid fever was at least that achieved with cparenterally administered whole cell vaccine preparations and cwas retained for at least three years.


Vaccine Strain Outer Membrane Protein Typhoid Fever Yersinia Enterocolitica Hybrid Molecule 


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  1. Agarwal, A., Kumar, S., Jaffe, R., Hone, D., Gross, M., and Sadoff, J. 1990. Oral Salmonella: malaria circumsporozoite recombinants induce specific CD8+ cytotoxic T cells. J. Exp. Med. 172:1083–1090.CrossRefGoogle Scholar
  2. Arias, C.F., Garcia, G., and Lopez, S. 1989. Priming for rotavirus neutralizing antibodies by a VP4 protein-derived synthetic peptide. J. Virol. 63:5393–5398.PubMedGoogle Scholar
  3. Bixler, G.S., Eby, R., Dermody, K.M., Woods, R.M., Seid, R.C., and Pillai, S. 1989. Synthetic peptide representing a T-cell epitope of CRM197 substitutes as carrier molecule in a Haemophilus influenzae type B (HIB) conjugate vaccine. In “Immunobiology of proteins and peptides V” (Atassi, M.Z., ed.) pp.175–180, Plenum Press, New York.Google Scholar
  4. Clements, J.D., and El-Morshidy, S. 1984. Construction of a potential oral live bivalent vaccine for typhoid fever and cholera-Escherichia coli-related diarrheas. Infect. Immun., 466:564–569.Google Scholar
  5. Curtiss, R. III, and Kelly, S.M. 1987. Salmonella typhimurium deletion mutants lacking adenylate cyclase and cyclic AMP receptor protein are avirulent and immunogenic. Infect. Immun. 55: 3035–3043.PubMedGoogle Scholar
  6. Dorman, C.J., Chatfield, S., Higgins, CF., Hayward, C., and Dougan, G. 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
  7. Ferreccio, C., Levine, M.M., Rodriguez, H., Contreras, R., and Chilean Typhoid Committee. 1989. Comparative efficacy of two, three, or four dose of Ty21a live oral typhoid vaccine in enteric-coated capsules: a field trial in an endemic area. J. Infect. Dis. 159:766–769.PubMedCrossRefGoogle Scholar
  8. Frenchick, P.J., Sabara, M.I.J., and Babiuk, L.A. 1989. Use of a viral nucleocapsid particle as a carrier for synthetic peptides. In Vaccine 89: modern approaches to new vaccines including prevention of AIDS (Lerner, R.A. et al, eds.) pp. 479–483, Cold Spring Harbor Laboratory, New York.Google Scholar
  9. Herrington, D.A., Van de Verg, L., Formal, S.B., Hale, T.L., Tall, B.D., Cryz, S.J., Tramont, E.C., and Levine, M.M. 1990. Studies in volunteers to evaluate candidate Shigella vaccines: further experience with a bivalent Salmonella typhi-Shigella sonne1i vaccine and protection conferred by previous Shigella sonnei disease. Vaccine 8:353–357.PubMedCrossRefGoogle Scholar
  10. Hone, D.M., Attridge, S.R., Forrest, B., Morona, R., Daniels, D., LaBrooy, J.T., Bartholomeusz, R.C.A., Shearman, D.J.C., and Hackett, J. 1988a. A galE via (Vi antigen-negative) mutant of Salmonella typhi Ty2 retains virulence in humans. Infect. Immun. 56:1326–1333.PubMedGoogle Scholar
  11. Hone, D., Attridge, S., van den Bosch, L., and Hackett, J. 1988b. A chromosomal integration system for stabilisation of heterologous genes in Salmonella based vaccine strains. Microb. Path. 5:407–418.CrossRefGoogle Scholar
  12. Kumar, S., Gorden, J., Flynn, J.L., Berzofsky, J.A., and Miller, L.H. 1990. Immunization of mice against Plasmodium vinckei with a combination of attenuated Salmonella typhimurium and malarial antigen Immunization of mice against Plasmodium vinckei with a combination of attenuated Salmonella typhimurium and malarial antigen. Infect. Immun. 58:3425–3429.PubMedGoogle Scholar
  13. Levine, M.M., Ferreccio, C., Black, R.E., Germanier, R, and Chilean Typhoid Committee. 1987a. Large-scale field trial of Ty21a live oral vaccine in enteric-coated capsule formulation. Lancet i: 1049–1052.CrossRefGoogle Scholar
  14. Levine, M.M., Herrington, D., Murphy, J.R., Morris, J.G., Losonsky, G., Tall, B., Lindberg, A.A., Svenson, S., Baqar, S., Edwards, M.F., and B. Stocker. 1987b. Safety, infectivity, immunogenicity, and in vivo stability of two attenuated auxotrophic mutant strains of Salmonella typhi, 541Ty and 543Ty, as live oral vaccines in humans. J. Clin. Invest. 79:888–902.PubMedCrossRefGoogle Scholar
  15. Majarian, W.R., Kasper, S.J., and Brey, R.N. 1989. Expression of heterologous epitopes as recombinant flagella on the surface of attenuated Salmonella. In “Vaccine 89:modern approaches to new vaccines including prevention of AIDS” (Lerner, R.A., et al, eds. ) pp. 277–281, Cold Spring Harbor Laboratory, New York.Google Scholar
  16. McGuiness, B., Barlow, A.K., Charles, I.N., Farley, J.E., Anilionis, A., Poolman, J.T., and Heckles, J.E. 1990. Deduced amino acid sequence of class I protein (porA) from three strains of Neisseria meningiditis. J. Exp. Med. 171:1871–1882.CrossRefGoogle Scholar
  17. Miller, S., and Mekalanos, J.J. 1990. Constitutive expression of the phoP regulon attenuates Salmonella virulence and survival within macrophages. J. Bacteriol. 172:2485–2490.PubMedGoogle Scholar
  18. Newton, S.M.C., Jacob, CO., and Stocker, B.A.D. 1989. Immune response to cholera toxin epitope inserted in Salmonella flagellin. Science 244:70–72.PubMedCrossRefGoogle Scholar
  19. O’Callaghan, D.O., Maskell, D., Liew, F.Y., Easmon, C.S.F., and Dougan, G. 1988. Characterization 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
  20. Poirier, T.P., Kehoe, M.A., and Beachey, E.H. 1988. Protective immunity evoked by oral administration of attenuated aroA Salmonella typhimurium expressing cloned streptococcal M protein. J. Exp. Med. 168:25–32.PubMedCrossRefGoogle Scholar
  21. Romero, P., Maryanski, J.L., Corradin, G., Nussenzweig, R.S., Nussenzweig, V., and Zavala, F. 1989. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protects against malaria. Nature (Lond.). 341:323–326CrossRefGoogle Scholar
  22. Sadoff, J.C., Ballou, W.R., Baron, L.S., Majarian, W.R., Brey, R.N., Hockmeyer, W.T., Young, J.F., Cryz, S.J., Ou, J., Lowell, G.H., and Chulay, J.D. 1988. Salmonella typhimurium vaccine expressing circumsporozoite protects against malaria. Science 240:336–338.PubMedCrossRefGoogle Scholar
  23. Sory, M., Hermand, P., Vaerman, J.P., and Cornells, G.R. 1990. Oral immunization of mice with a live recombinant Yersinia enterocolitica 0:9 strain that produces the cholera toxin B subunit. Infect. Immun. 58:2420–2428.PubMedGoogle Scholar
  24. Tacket, C.O., Forrest, B., Morona, R., Attridge, S.R., LaBrooy, J., Tall, B.D., Reymann, M., Rowley, D., and Levine, M.M. 1990. Safety, immunogenicity, and efficacy against cholera challenge in humans of a typhoid-cholera hybrid vaccine derived from Salmonella typhi Ty21a. Infect. Immun. 58:1620–1627.PubMedGoogle Scholar
  25. Tite, J.P., Gao, X.-M., Hughes-Jenkins, CM., Lipscombe, M., O’Callaghan, D., and Dougan, G. 1990. Antiviral 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
  26. van der Werf, S., Charbit, A., Leclerc, C., Mimic, V., Ronco., J., Girard, M., and Hofnung, M. 1990. Critical role of neighboring sequences on the immunogenicity of the C3 poliovirus neutralization epitope expressed at the surface of recombinant bacteria. Vaccine 8:269–277.PubMedCrossRefGoogle Scholar
  27. Wahdan, M.H., Serie, C., Cerisier, Y., Sallam, S., and Germanier, R. 1982. A controlled field trial of live Salmonella typhi strain Ty21a oral vaccine against typhoid: three-year results. J. Infect. Dis. 145:292–295.PubMedCrossRefGoogle Scholar
  28. Wei, L.-N., and Joys, T.M. 1985. Covalent structure of three phase-1 flagellar filament proteins of Salmonella. J. Mol. Biol. 186:791–803.PubMedCrossRefGoogle Scholar
  29. Wu., J., Newton, S., Judd, A., Stocker, B., and Robinson, W.S. 1989. Expression of immunogenic epitopes of hepatitis B surface antigen with hybrid flagellin proteins by a vaccine strain of Salmonella. Proc. Nat. Acad. Sci.(USA) 86:4726–4730.CrossRefGoogle Scholar
  30. Yang, D.M., Fairweather, N., Button, L.L., McMaster, W.R., Kahl, L.P., and Liew, F.Y. 1990. Oral Salmonella typhimurium (aroA) vaccine expressing a major leishmanial surface protein (gp63) preferentially induces T helper cells and protective immunity against leishmaniasis. J. Immunol. 145:2281–2285.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Robert N. Brey
    • 1
  • Garvin S. Bixler
    • 1
  • James P. Fulginiti
    • 1
  • Deborah A. Dilts
    • 1
  • Marta I. J. Sabara
    • 1
  1. 1.Praxis BiologicsRochesterUSA

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