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Infect Immun. Feb 1997; 65(2): 452–456.
PMCID: PMC174616

Safety of live oral Salmonella typhi vaccine strains with deletions in htrA and aroC aroD and immune response in humans.


A single-dose, oral Salmonella typhi vaccine strain has been sought as a carrier or vector of cloned genes encoding protective antigens of other pathogens. Such a hybrid vaccine, administered orally, would stimulate immune responses both at the mucosal surface and in the systemic compartment and would potentially provide protection against multiple pathogens. S. typhi CVD 908 and CVD 906, which harbor deletions in aroC and aroD, were further engineered by deletion in htrA to produce strains CVD 908-htrA and CVD 906-htrA, which are unable to sustain growth and are severely impaired in their ability to survive in host tissues. These strains were fed to humans at doses of 5 x 10(7) to 5 x 10(9) CFU with buffer, and safety and immune responses were assessed. CVD 908-htrA and CVD 906-htrA were well tolerated in volunteers; mild diarrhea in 3 of 36 volunteers and mild fever in 1 volunteer were the only notable adverse responses. The vaccine strains were not detected in blood cultures and only transiently detected in stool. Serum immune responses to S. typhi lipopolysaccharide and H antigens were observed in 75 to 100% of volunteers who received 5 x 10(8) to 5 x 10(9) CFU, and cells secreting S. typhi-specific antibodies were found in all volunteers after ingestion of either strain. Sixty-three percent to 83% of volunteers developed lymphoproliferative responses to S. typhi flagellar and particulate antigens after the higher doses. These studies demonstrate the potential of CVD 908-htrA as a live vector for the delivery of heterologous genes, and a clinical trial of such a construct is planned.

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Selected References

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  • Brown A, Hormaeche CE, Demarco de Hormaeche R, Winther M, Dougan G, Maskell DJ, Stocker BA. An attenuated aroA Salmonella typhimurium vaccine elicits humoral and cellular immunity to cloned beta-galactosidase in mice. J Infect Dis. 1987 Jan;155(1):86–92. [PubMed]
  • Chatfield SN, Fairweather N, Charles I, Pickard D, Levine M, Hone D, Posada M, Strugnell RA, Dougan G. Construction of a genetically defined Salmonella typhi Ty2 aroA, aroC mutant for the engineering of a candidate oral typhoid-tetanus vaccine. Vaccine. 1992;10(1):53–60. [PubMed]
  • Clements JD, 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. [PMC free article] [PubMed]
  • Formal SB, Baron LS, Kopecko DJ, Washington O, Powell C, Life CA. Construction of a potential bivalent vaccine strain: introduction of Shigella sonnei form I antigen genes into the galE Salmonella typhi Ty21a typhoid vaccine strain. Infect Immun. 1981 Dec;34(3):746–750. [PMC free article] [PubMed]
  • Germanier R, Füer E. Isolation and characterization of Gal E mutant Ty 21a of Salmonella typhi: a candidate strain for a live, oral typhoid vaccine. J Infect Dis. 1975 May;131(5):553–558. [PubMed]
  • Girón JA, Xu JG, González CR, Hone D, Kaper JB, Levine MM. Simultaneous expression of CFA/I and CS3 colonization factor antigens of enterotoxigenic Escherichia coli by delta aroC, delta aroD Salmonella typhi vaccine strain CVD 908. Vaccine. 1995 Jul;13(10):939–946. [PubMed]
  • Gonzalez C, Hone D, Noriega FR, Tacket CO, Davis JR, Losonsky G, Nataro JP, Hoffman S, Malik A, Nardin E, et al. Salmonella typhi vaccine strain CVD 908 expressing the circumsporozoite protein of Plasmodium falciparum: strain construction and safety and immunogenicity in humans. J Infect Dis. 1994 Apr;169(4):927–931. [PubMed]
  • Hohmann EL, Oletta CA, Killeen KP, Miller SI. 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. [PubMed]
  • Hoiseth SK, Stocker BA. Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature. 1981 May 21;291(5812):238–239. [PubMed]
  • Hone DM, Harris AM, Chatfield S, Dougan G, Levine MM. Construction of genetically defined double aro mutants of Salmonella typhi. Vaccine. 1991 Nov;9(11):810–816. [PubMed]
  • Hone DM, Tacket CO, Harris AM, Kay B, Losonsky G, Levine MM. Evaluation in volunteers of a candidate live oral attenuated Salmonella typhi vector vaccine. J Clin Invest. 1992 Aug;90(2):412–420. [PMC free article] [PubMed]
  • Johnson K, Charles I, Dougan G, Pickard D, O'Gaora P, Costa G, Ali T, Miller I, Hormaeche C. The role of a stress-response protein in Salmonella typhimurium virulence. Mol Microbiol. 1991 Feb;5(2):401–407. [PubMed]
  • Killar LM, Eisenstein TK. Immunity to Salmonella typhimurium infection in C3H/HeJ and C3H/HeNCrlBR mice: studies with an aromatic-dependent live S. typhimurium strain as a vaccine. Infect Immun. 1985 Mar;47(3):605–612. [PMC free article] [PubMed]
  • Levine MM, Herrington D, Murphy JR, Morris JG, Losonsky G, Tall B, Lindberg AA, Svenson S, Baqar S, Edwards MF, et al. 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. [PMC free article] [PubMed]
  • Smith BP, Reina-Guerra M, Hoiseth SK, Stocker BA, Habasha F, Johnson E, Merritt F. Aromatic-dependent Salmonella typhimurium as modified live vaccines for calves. Am J Vet Res. 1984 Jan;45(1):59–66. [PubMed]
  • Sztein MB, Wasserman SS, Tacket CO, Edelman R, Hone D, Lindberg AA, Levine MM. Cytokine production patterns and lymphoproliferative responses in volunteers orally immunized with attenuated vaccine strains of Salmonella typhi. J Infect Dis. 1994 Dec;170(6):1508–1517. [PubMed]
  • Tacket CO, Forrest B, Morona R, Attridge SR, LaBrooy J, Tall BD, Reymann M, Rowley D, Levine MM. Safety, immunogenicity, and efficacy against cholera challenge in humans of a typhoid-cholera hybrid vaccine derived from Salmonella typhi Ty21a. Infect Immun. 1990 Jun;58(6):1620–1627. [PMC free article] [PubMed]
  • Tacket CO, Hone DM, Curtiss R, 3rd, Kelly SM, Losonsky G, Guers L, Harris AM, Edelman R, Levine MM. 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. [PMC free article] [PubMed]
  • Tacket CO, Hone DM, Losonsky GA, Guers L, Edelman R, Levine MM. Clinical acceptability and immunogenicity of CVD 908 Salmonella typhi vaccine strain. Vaccine. 1992;10(7):443–446. [PubMed]
  • Walker MJ, Rohde M, Timmis KN, Guzmán CA. Specific lung mucosal and systemic immune responses after oral immunization of mice with Salmonella typhimurium aroA, Salmonella typhi Ty21a, and invasive Escherichia coli expressing recombinant pertussis toxin S1 subunit. Infect Immun. 1992 Oct;60(10):4260–4268. [PMC free article] [PubMed]

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