• Type: Live, attenuated vaccine
• Antigen: The antigen used was aro-deleted S. Typhi, a strain designated as CVD 908 (Tacket and Levine, 2007).
• AroD gene engineering:
  • Type: Recombinant protein preparation
  • Description: Inactivation of AroD results in attenuation, and the deletions of both AroC and AroD provide a high level of safety against restoration of pathogenicity by recombination. An aroC/aroD-deleted derivative of S. Typhi strain Ty2 (the parent strain of Ty21a) is designated the strain "CVD 908" (Tacket and Levine, 2007).
  • Detailed Gene Information: Click Here.
• AroC gene engineering:
  • Type: Recombinant protein preparation
  • Description: Inactivation of AroC results in attenuation, and the deletions of both AroC and AroD provide a high level of safety against restoration of pathogenicity by recombination. An aroC/aroD-deleted derivative of S. Typhi strain Ty2 (the parent strain of Ty21a) is designated the strain "CVD 908" (Tacket and Levine, 2007).
  • Detailed Gene Information: Click Here.
• Preparation: CVD 908 was created by deleting both aroC and aroD, preventing restoration of pathogenicity by recombination (Tacket and Levine, 2007).
• Virulence: After a single dose of the vaccine (5 × 10^4 or 5 × 10^5 cfu), vaccine bacteremia was not detected in serial blood cultures. Half of the subjects tested with this dose developed serum IgG anti–lipopolysaccharide antibodies and IgA anti-LPS antibody-secreting cells (Tacket and Levine, 2007).
• Description: The aromatic metabolites, such as aroC and aroD, force Salmonella to be nutritionally dependent on p-aminobenzoic acid and 2,3-dihydroxy, both of which are not available in mammilian tissues, preventing proliferation in the host cells (Tacket and Levine, 2007).

• Vaccine Ontology ID: VO_0002865
• Type: Live, attenuated vaccine
• Antigen: The antigen was htrA-deleted S.Typhi (Tacket and Levine, 2007).
• AroC gene engineering:
  • Type: Recombinant protein preparation
  • Description: HtrA was deleted in Salmonella organisms, which created a mutant that was less virulent and more susceptible to oxidative killing. HtrA encodes a heat-shock protein in Salmonella (Tacket and Levine, 2007).
    
    
  • Detailed Gene Information: Click Here.
• Preparation: Formation of CVD 908-htrA was conducted from original CVC 908, and the vaccine created consisted of live lyophilized organisms in single-dose glass vials to be resuspended in buffer solution (Tacket and Levine, 2007).
  
• Virulence: CVD 908-htrA retained the immunogenicity of the parent CVD 908, but no vaccine bacteremias were detected among people who received a single dose of 5 × 10^7, 5 × 10^8, or 5 × 10^9 cfu, despite surveillance for bacteremias after vaccination. The immune responses measured by seroconversion rates with IgG anti-LPS after vaccination with CVD 908 and CVD 908-htrA were very similar. Most volunteers developed ASC responses, regardless of the vaccine strain received. Some lymphoproliferative responses to flagella and particulate antigen after CVD 908-htrA vaccination were also observed (Tacket and Levine, 2007).
  

• Vaccine Ontology ID: VO_0004138
• Type: Live, attenuated vaccine
• Status: Licensed
• HtrA gene engineering:
  • Type: Recombinant protein preparation
  • Description: CVD 909 was constructed by replacing the native promoter of tviA with the strong constitutive promoter Ptac (Wang et al., 2000).
  • Detailed Gene Information: Click Here.
• Preparation: S. Typhi CVD 909 was constructed to express the Vi-antigen. This involved a deletion in the promoter region of tviA and an insertion of the sacB-neo cassette, introduced into the chromosome of CVD 908-htrA by homologous recombination. The replacement of the sacB-neo cassette allowed the replacement of the promoter region with the Ptac promoter in a second homologous recombination event (Wang et al., 2000).

• Product Name: Typhoid Vi Polysaccharide Vaccine
• Tradename: Typhim Vi
• Manufacturer: Sanofi Pasteur SA
• Vaccine Ontology ID: VO_0000104
• CDC CVX code: 101
• Type: Subunit vaccine
• Status: Licensed
• Location Licensed: USA (License #1724)
• Host Species for Licensed Use: Human
• Antigen: The Vi-antigen is a polysaccharide capsule found only in S. enterica serovars Dublin, Typhi, and Paratyphi C The Vi-antigen is a polysaccharide capsule found only in S. enterica serovars Dublin, Typhi, and Paratyphi C (Cheminay and Hensel, 2007).
• Preservative: Phenol
• Immunization Route: Intramuscular injection (i.m.)
• Storage: Store at 2° to 8°C (35° to 46°F). DO NOT FREEZE.
• Approved Age for Licensed Use: Two years of age and older.
• Contraindication: TYPHIM Vi VACCINE IS CONTRAINDICATED IN PATIENTS WITH A HISTORY OF HYPERSENSITIVITY TO ANY COMPONENT OF THIS VACCINE (Typhim Vi).
• Description: Contains the cell surface Vi polysaccharide extracted from Salmonella enterica serovar Typhi, S typhi Ty2 strain. The organism is grown in a semi-synthetic medium without animal proteins. The capsular polysaccharide is precipitated from the concentrated culture supernatant by the addition of hexadecyltrimethylammonium bromide and the product is purified by differential centrifugation and precipitation (Typhim Vi).

• Product Name: Typhoid Vaccine Live Oral Ty21a
• Tradename: Vivotif
• Manufacturer: Berna Biotech, Ltd
• Vaccine Ontology ID: VO_0000120
• CDC CVX code: 25
• Type: Live, attenuated vaccine
• Status: Licensed
• Location Licensed: USA (License # 1632)
• Host Species for Licensed Use: Human
• Antigen: The antigen is live, attenuated strain Ty21a (Levine et al., 2007).
  
  
  
• Preparation: Ty21a in enteric-coated capsules was created with 2 × 10^9–5 × 10^9 cfu of Ty21 (Levine et al., 2007).
• Immunization Route: Oral
• Storage: between 2 °C and 8 °C (35.6 °F– 46.4 °F).
• Approved Age for Licensed Use: 6 years of age and older.
• Contraindication: Hypersensitivity to any component of the vaccine or the enteric-coated capsule (FDA: Vivotif).
• Description: Indication: VIVOTIF is used for immunization of adults and children greater than 6 years of age against disease caused by Salmonella typhi (FDA: Vivotif).

Human Response

• Vaccination Protocol: Each vaccine was ingested and contained 2.2 3 10^8 organisms of lyophilized vaccine. A second lower dose contained 5 3 10^7 viable organisms. Volunteers fasted for 90 minutes before and after vaccination. A placebo of sodium bicarbonate was also included (Tacket et al., 2000).
  
• Immune Response: After a single oral dose, CVD 908-htrA stimulates vigor-
  ous mucosal, humoral, and cellular immune responses at levels (Tacket et al., 2000).
• Side Effects: Two volunteers had diarrhea in the first 24 h after ingesting vaccine. Three volunteers had
  diarrhea that occurred later (Tacket et al., 2000).
• Efficacy: Recipients of the high dose of CVD 908-htrA had a mean of 189 anti-LPS IgA ASC per 10^6 PBMC. Vigorous IgM and IgG ASC responses were detected among vaccinees. ASC-producing an-ti-H antigen IgA occurred in a majority of participants (Tacket et al., 2000).
• Host human IgA response
  • Description: ASCs producing IgA anti-LPS were detected in 100% of recipients of the high-dose vaccine and in 92% of recipients of the lower-dose vaccine. ASCs producing IgA anti-H antigen occurred in 79% and 73% of high- and lower-dose vaccine recipients, respectively (Tacket and Levine, 2007).
  • Detailed Gene Information: Click Here.

Human Response

• Vaccination Protocol: In this study, 80 healthy adult outpatient volunteers were randomized to receive, with buffer, a single oral administration of high-dose CVD 908-htrA (4.5 × 108 cfu), lower-dose CVD 908-htrA (5 × 107 cfu), or placebo. On day 28, there was a crossover in which the volunteers who had ingested CVD 908-htrA vaccine on day 0 received placebo and those who had received placebo on day 0 received CVD 908-htrA vaccine in either the high or the lower dose (Tacket and Levine, 2007).
• Side Effects: The incidence of adverse effects was the same in recipients of placebo, high-dose vaccine, or lower-dose vaccine after vaccination. Diarrhea, a potential concern observed in a small number of vaccine recipients in the uncontrolled, phase 1 study, occurred in 3 (4%) of 76 placebo recipients, 1 (3%) of 39 lower-dose vaccine recipients, and 4 (10%) of 39 high-dose vaccine recipients (a statistically insignificant difference). However, in a secondary analysis of the incidence of symptoms in the first 7 days after vaccination, recipients of the high-dose vaccine were found to be slightly more likely to have had diarrhea (8%) than were recipients of placebo (0%) (P = .04). No recipient of the lower-dose vaccine had diarrhea in the first 7 days after vaccination (Tacket and Levine, 2007).
• Host human IgA response
  • Description: ASCs producing IgA anti-LPS were detected in 100% of recipients of the high-dose vaccine and in 92% of recipients of the lower-dose vaccine. ASCs producing IgA anti-H antigen occurred in 79% and 73% of high- and lower-dose vaccine recipients, respectively (Tacket and Levine, 2007).
  • Detailed Gene Information: Click Here.

Human Response

• Vaccination Protocol: 24 volunteers received a single oral dose of CVD 909 of 10^6–10^9 cfu, and 8 adults received 2 doses of 6 × 10^9 cfu per dose with buffer 14 days apart (Tacket and Levine, 2007).
• Immune Response: All volunteers tested developed IgA anti-LPS ASCs. However, only 1 of the volunteers who ingested a single dose and only 1 of the 8 volunteers who ingested 2 doses developed serum IgG anti-Vi .However, IgA anti-Vi ASC responses were detected in a majority of volunteers who received 10^8–10^9 cfu of CVD 909. These Vi-specific ASC responses provided evidence that the Vi antigen was expressed and immunologically processed, even if serum antibody responses were realitvely small (Tacket and Levine, 2007).
• Side Effects: Not noted.

Human Response

• Side Effects: The most common side effects reported are: injection site reactions, fever, headache, nausea, and malaise (Typhim Vi).
• Efficacy: The overall protective efficacy of Typhim Vi vaccine was 74% confirmed by a blood culture of confirmed cases of typhoid fever during 20 months of post-vaccination follow-up (Typhim Vi).

Human Response

• Vaccination Protocol: Two trials were completed with Ty21a: In the first, Participants were randomly allocated to receive, 1 week apart, either 2 doses of Ty21a in enteric-coated capsules, 1 dose of Ty21a and 1 dose of placebo, or 2 doses of placebo. In the second, participants were randomly allocated to receive 3 doses of vaccine in 1 of 2 different formulations or placebo. One formulation of Ty21a was enteric-coated capsules, and the other was a triad of gelatin capsules, with 1 containing lyophilized vaccine and the other 2 containing NaHCO3 buffer.
• Persistence: Not noted.
• Immune Response: Doses of Ty21a in capsules stimulates a form of antibody-dependent cellular cytotoxicity, in which IgA antibodies provide the specificity for cells to kill Salmonella organisms. Ty21a stimulates strong classical cell-mediated immune responses involving specific T cells that are believed to function through different effector mechanisms, such as production of IFN-gamma and other cytokines when stimulated by inactivated whole bacilli and purified S. Typhi flagella and the appearance of cytotoxic T cells that kill target cells infected with S. Typhi (Levine et al., 2007). Unless a complete immunization schedule is followed, an optimum immune response may not be achieved (FDA: Vivotif).
• Side Effects: The most common side effects reported were: abdominal pain, nausea, headache, fever, diarrhea, vomiting and skin rash (FDA: Vivotif).
• Efficacy: Results from clinical studies indicate that adults and children greater than 6 years of age may be protected against typhoid fever following the oral ingestion of 4 doses of VIVOTIF (FDA: Vivotif).

Mouse Response

• Host Strain: BALB/c
• Vaccination Protocol: Three groups of 6-week-old BALB/c mice were immunized once intranasally with 10^10 CFU of either serovar Typhi strain CVD 908-htrA or CVD 909 or PBS (control) (Wang et al., 2000).
• Immune Response: The mean titer of IgG anti-Vi was much higher in the mice that received CVD 909. However, GMTs of O antibody after immunization were quite similar in the two groups (CVD 909 and CDV 908-htrA) (Wang et al., 2000).
• Side Effects: Not noted.
• Challenge Protocol: Mice were challenged with wild-type serovar Typhi strain Ty2 thirty days after primary immunization (Wang et al., 2000).
• Efficacy: A single mucosal dose of CVD 909 conferred significantly greater protection than CVD 908-htrA (Wang et al., 2000).