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. 1997 Aug;65(8):3381–3385. doi: 10.1128/iai.65.8.3381-3385.1997

Safety and immunogenicity in humans of an attenuated Salmonella typhi vaccine vector strain expressing plasmid-encoded hepatitis B antigens stabilized by the Asd-balanced lethal vector system.

C O Tacket 1, S M Kelly 1, F Schödel 1, G Losonsky 1, J P Nataro 1, R Edelman 1, M M Levine 1, R Curtiss 3rd 1
PMCID: PMC175478  PMID: 9234801

Abstract

Attenuated Salmonella typhi organisms which express genes encoding protective antigens of other pathogens have been developed for use as experimental oral vaccines. A delta asd S. typhi strain attenuated by deletions in cya, crp, and cdt which contains hepatitis B core (HBc) and pre-S genes encoded on an Asd+ pBR-based plasmid vector was constructed. Healthy adult volunteers ingested a single dose of 5 x 10(5) to 5 x 10(8) CFU of strain chi4073 (delta cya delta crp delta cdt S. typhi Ty2), 6 x 10(7) or 1 x 10(9) CFU of strain chi4632(pYA3149), a further derivative of chi4073 deleted in asd and containing the Asd+ vector without the HBc-pre-S fusion, or 3 x 10(7) or 7 x 10(8) CFU of strain X4632(pYA3167), a derivative containing the vector with the HBc-pre-S fusion. Chi4073 was generally well tolerated by 22 volunteers. No volunteer had fever or positive blood cultures; 4 of 22 volunteers shed vaccine organisms in the stool in the first 48 h only. Two of 18 volunteers who received one of the plasmid-containing derivatives of chi4073 developed low-grade fevers on day 10 or 12 after ingestion. One of these volunteers had positive blood cultures on days 7 and 8. Seven of these 18 volunteers had vaccine organisms detected in their stools in the first 48 h only. Most volunteers developed S. typhi-specific serum responses and developed S. typhi-specific antibody-secreting cells. However, no volunteer developed serum antibody to hepatitis pre-S or pre-S-specific antibody-secreting cells. Although the parent strain chi4073 was well tolerated, induced immunoglobulin G seroconversion to S. typhi lipopolysaccharide in 80 to 100% of vaccinees and stimulated specific IgA-secreting lymphocytes in 80 to 100% of vaccinees given a single oral dose of 2 x 10(7) and 5 x 10(8) CFU, chi4073 derivatives containing the Asd+ vector with and without sequences encoding the HBc-pre-S fusion caused occasional febrile reactions at high doses and did not stimulate detectable immune responses to hepatitis B antigens.

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Selected References

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  1. Alper M. D., Ames B. N. Transport of antibiotics and metabolite analogs by systems under cyclic AMP control: positive selection of Salmonella typhimurium cya and crp mutants. J Bacteriol. 1978 Jan;133(1):149–157. doi: 10.1128/jb.133.1.149-157.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Botsford J. L., Harman J. G. Cyclic AMP in prokaryotes. Microbiol Rev. 1992 Mar;56(1):100–122. doi: 10.1128/mr.56.1.100-122.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clements J. D., El-Morshidy S. Construction of a potential live oral bivalent vaccine for typhoid fever and cholera-Escherichia coli-related diarrheas. Infect Immun. 1984 Nov;46(2):564–569. doi: 10.1128/iai.46.2.564-569.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Curtiss R., 3rd, Kelly S. M., Gulig P. A., Nakayama K. Selective delivery of antigens by recombinant bacteria. Curr Top Microbiol Immunol. 1989;146:35–49. doi: 10.1007/978-3-642-74529-4_4. [DOI] [PubMed] [Google Scholar]
  5. Curtiss R., 3rd, Kelly S. M. Salmonella typhimurium deletion mutants lacking adenylate cyclase and cyclic AMP receptor protein are avirulent and immunogenic. Infect Immun. 1987 Dec;55(12):3035–3043. doi: 10.1128/iai.55.12.3035-3043.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Delos S., Villar M. T., Hu P., Peterson D. L. Cloning, expression, isolation and characterization of the pre-S domains of hepatitis B surface antigen, devoid of the S protein. Biochem J. 1991 Jun 1;276(Pt 2):411–416. doi: 10.1042/bj2760411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Forrest B. D. Identification of an intestinal immune response using peripheral blood lymphocytes. Lancet. 1988 Jan 16;1(8577):81–83. doi: 10.1016/s0140-6736(88)90284-x. [DOI] [PubMed] [Google Scholar]
  8. Hohmann E. L., Oletta C. A., Killeen K. P., Miller S. I. phoP/phoQ-deleted Salmonella typhi (Ty800) is a safe and immunogenic single-dose typhoid fever vaccine in volunteers. J Infect Dis. 1996 Jun;173(6):1408–1414. doi: 10.1093/infdis/173.6.1408. [DOI] [PubMed] [Google Scholar]
  9. Hone D. M., Tacket C. O., Harris A. M., Kay B., Losonsky G., Levine M. M. Evaluation in volunteers of a candidate live oral attenuated Salmonella typhi vector vaccine. J Clin Invest. 1992 Aug;90(2):412–420. doi: 10.1172/JCI115876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hornick R. B., Greisman S. E., Woodward T. E., DuPont H. L., Dawkins A. T., Snyder M. J. Typhoid fever: pathogenesis and immunologic control. N Engl J Med. 1970 Sep 24;283(13):686–691. doi: 10.1056/NEJM197009242831306. [DOI] [PubMed] [Google Scholar]
  11. Kelly S. M., Bosecker B. A., Curtiss R., 3rd Characterization and protective properties of attenuated mutants of Salmonella choleraesuis. Infect Immun. 1992 Nov;60(11):4881–4890. doi: 10.1128/iai.60.11.4881-4890.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Levine M. M., Galen J., Barry E., Noriega F., Chatfield S., Sztein M., Dougan G., Tacket C. Attenuated Salmonella as live oral vaccines against typhoid fever and as live vectors. J Biotechnol. 1996 Jan 26;44(1-3):193–196. doi: 10.1016/0168-1656(95)00094-1. [DOI] [PubMed] [Google Scholar]
  13. 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. 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. 1987 Mar;79(3):888–902. doi: 10.1172/JCI112899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nardelli-Haefliger D., Kraehenbuhl J. P., Curtiss R., 3rd, Schodel F., Potts A., Kelly S., De Grandi P. Oral and rectal immunization of adult female volunteers with a recombinant attenuated Salmonella typhi vaccine strain. Infect Immun. 1996 Dec;64(12):5219–5224. doi: 10.1128/iai.64.12.5219-5224.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ross E. M., Gilman A. G. Biochemical properties of hormone-sensitive adenylate cyclase. Annu Rev Biochem. 1980;49:533–564. doi: 10.1146/annurev.bi.49.070180.002533. [DOI] [PubMed] [Google Scholar]
  16. Schwartzel E. H., Jr, Bachman S., Levine R. A. Cyclic nucleotide activity in gastrointestinal tissues and fluids. Anal Biochem. 1977 Apr;78(2):395–405. doi: 10.1016/0003-2697(77)90100-2. [DOI] [PubMed] [Google Scholar]
  17. Schödel F., Kelly S. M., Peterson D. L., Milich D. R., Curtiss R., 3rd Hybrid hepatitis B virus core-pre-S proteins synthesized in avirulent Salmonella typhimurium and Salmonella typhi for oral vaccination. Infect Immun. 1994 May;62(5):1669–1676. doi: 10.1128/iai.62.5.1669-1676.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Schödel F., Milich D. R., Will H. Hepatitis B virus nucleocapsid/pre-S2 fusion proteins expressed in attenuated Salmonella for oral vaccination. J Immunol. 1990 Dec 15;145(12):4317–4321. [PubMed] [Google Scholar]
  19. Schödel F., Peterson D., Hughes J., Milich D. R. A virulent Salmonella expressing hybrid hepatitis B virus core/pre-S genes for oral vaccination. Vaccine. 1993;11(2):143–148. doi: 10.1016/0264-410x(93)90010-u. [DOI] [PubMed] [Google Scholar]
  20. Tacket C. O., Hone D. M., Curtiss R., 3rd, Kelly S. M., Losonsky G., Guers L., Harris A. M., Edelman R., Levine M. M. Comparison of the safety and immunogenicity of delta aroC delta aroD and delta cya delta crp Salmonella typhi strains in adult volunteers. Infect Immun. 1992 Feb;60(2):536–541. doi: 10.1128/iai.60.2.536-541.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Tacket C. O., Hone D. M., Losonsky G. A., Guers L., Edelman R., Levine M. M. Clinical acceptability and immunogenicity of CVD 908 Salmonella typhi vaccine strain. Vaccine. 1992;10(7):443–446. doi: 10.1016/0264-410x(92)90392-w. [DOI] [PubMed] [Google Scholar]
  22. Van de Verg L., Herrington D. A., Murphy J. R., Wasserman S. S., Formal S. B., Levine M. M. Specific immunoglobulin A-secreting cells in peripheral blood of humans following oral immunization with a bivalent Salmonella typhi-Shigella sonnei vaccine or infection by pathogenic S. sonnei. Infect Immun. 1990 Jun;58(6):2002–2004. doi: 10.1128/iai.58.6.2002-2004.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

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