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Immunogenicity, Safety and Tolerability of the Typhoid Fever Vaccine Candidate M01ZH09 in Healthy Adults

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Emergent BioSolutions
ClinicalTrials.gov Identifier:
NCT00679172
First received: May 14, 2008
Last updated: June 6, 2017
Last verified: June 2017
  Purpose
This study is to investigate the safety, tolerability and immunogenicity of the typhoid fever vaccine candidate M01ZH09 manufactured at commercial scale, at a new manufacturing facility. The vaccine will be delivered as a single oral dose to healthy, typhoid vaccine-naïve adults.

Condition Intervention Phase
Typhoid Biological: Dose of 5.0 x 10^9 CFU (Cohort 1) Biological: Dose of 7.5 x 10^9 CFU (Cohort 2) Biological: Dose of 1.1 x 10^10 CFU (Cohort 3) Biological: Dose of of 1.7 x 10^10 CFU (Cohort 4) Other: Placebo (Cohorts 1-4 pooled) Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Participant, Investigator, Outcomes Assessor
Primary Purpose: Prevention
Official Title: A Randomised, Double-blind, Placebo-controlled, Single Dose, Dose Escalation Study to Determine the Immunogenicity, Safety and Tolerability of S. Typhi (Ty2 aroC‾ssaV‾) ZH9 at Doses of 5.0 x 10E9 CFU, 7.5 x 10E9 CFU, 1.1 x 10E10 and 1.7 x 10E10 CFU and 1.7 x 10E10 CFU, Following Oral Administration to Healthy, Typhoid Vaccine naïve Subjects in the USA.

Resource links provided by NLM:


Further study details as provided by Emergent BioSolutions:

Primary Outcome Measures:
  • Number and Proportion of Subjects Reporting Suspected Unexpected Serious Adverse Reactions. [ Time Frame: From start of dosing to 28 days post-dosing. ]
    Number and proportion of subjects reporting suspected unexpected serious adverse reactions (SUSARs).

  • Number and Proportion of Subjects Experiencing Symptomatic Fever. [ Time Frame: From start of dosing to 14 days post-dosing. ]
    Number and proportion of subjects experiencing symptomatic (e.g., chills, rigors, sweating, headache, myalgia etc.) elevated body temperature of 38.0°C or more in the 14 days following dosing.

  • Number of Subjects Having Clinically Significant Changes in Laboratory Test Parameters. [ Time Frame: From start of dosing to 28 days post-dosing. ]
    Number of subjects having clinically significant changes in clinical laboratory test parameters.

  • Number of Subjects Reporting Treatment-related TEAEs. [ Time Frame: From start of dosing to 28 days post-dosing. ]
    Number of subjects having TEAEs considered by the principal investigator to be "possibly" or "probably" related to treatment.

  • Number and Proportion of Subjects Experiencing Bacteraemia. [ Time Frame: From start of dosing to 28 days post-dosing. ]
    Number and proportion of subjects experiencing a proven bacteraemia attributed to the vaccine strain S. typhi (Ty2 aroC‾ssaV‾) ZH9.

  • Number of Subjects Having Shedding in Stool of Salmonella Typhi (S. Typhi) (Ty2 aroC‾ssaV‾) ZH9. [ Time Frame: Beyond 7 days post-dosing through 14 days post-dosing (Cohorts 1-3) or through 21 days post-dosing (Cohort 4). ]
    Number of subjects having shedding in stool of S. typhi (Ty2 aroC‾ssaV‾) ZH9. Subjects were evaluated beyond Day 14 only in Cohort 4.

  • Number and Proportion of Subjects Developing an Immune Response as Determined by the Level of IgG and/or IgA Antibodies for S. Typhi Lipopolysaccharide (LPS). [ Time Frame: From baseline (pre-dose) to Days 14 or 28 (IgG) or to Days 7 or 14 (IgA). ]
    Number and proportion of subjects with increase of 70% (fold change of 1.7) in S. typhi LPS-specific serum IgG at Days 14 or 28 AND/OR increase of 50% (fold change of 1.5) in S. typhi LPS-specific serum IgA at Days 7 or 14. Serum IgG and IgA were assayed using enzyme-linked immunosorbent assay (ELISA).


Secondary Outcome Measures:
  • Number and Proportion of Subjects Developing an Immune Response as Determined by the Level of IgA Antibodies for S. Typhi LPS. [ Time Frame: From baseline (pre-dose) to Days 7 or 14. ]
    Number and proportion of subjects with increase of 50% (fold change of 1.5) in S. typhi LPS-specific serum IgA at Days 7 or 14. Serum IgA was assayed using ELISA.

  • Number and Proportion of Subjects Developing an Immune Response as Determined by the Level of IgG Antibodies for S. Typhi LPS. [ Time Frame: From baseline (pre-dose) to Days 14 or 28. ]
    Number and proportion of subjects with increase of 70% (fold change of 1.7) in S. typhi LPS-specific serum IgG at Days 14 or 28. Serum IgG was assayed using ELISA.

  • Number and Proportion of Subjects Developing an Immune Response as Determined by the Level of IgG Antibodies for S. Typhi LPS. [ Time Frame: From baseline (pre-dose) to Days 7, 14, or 28. ]
    Number and proportion of subjects with an increase of 70% (fold change of 1.7) in S. typhi LPS-specific serum IgG at Days 7, 14 or 28. Serum IgG was assayed using ELISA.

  • Number and Proportion of Subjects Developing an Immune Response at the Target Dose of 7.5 x 10^9 CFU (Cohort 2) as Determined by the Number of Antibody Secreting Cells (ASCs) Secreting IgA and/or Fold Change in IgG. [ Time Frame: At Day 7 (IgA); and from baseline (pre-dose) to Day 28 (IgG). ]
    Number and proportion of subjects with ≥ 4 ASCs per 10^6 peripheral blood mononuclear cells (PBMCs) at Day 7 secreting IgA specific for S. typhi LPS (detected by enzyme-linked immunospot assay [ELISPOT]) AND/OR 4-fold increase for serum IgG on Day 28 compared to baseline (assay using endpoint titre ELISA).

  • Number and Proportion of Subjects Developing an Immune Response at the Target Dose of 7.5 x 10^9 CFU (Cohort 2) as Determined by the Number of ASCs Secreting IgA. [ Time Frame: Day 7. ]
    Number and proportion of subjects with ≥ 4 ASCs per 10^6 PBMCs at Day 7 secreting IgA specific for S. typhi LPS (detected by ELISPOT).

  • Number and Proportion of Subjects Developing an Immune Response at the Target Dose of 7.5 x 10^9 CFU (Cohort 2) as Determined by the Fold Change in IgG. [ Time Frame: From baseline (pre-dose) to Day 28. ]
    Number and proportion of subjects with 4-fold increase for serum IgG on Day 28 compared to baseline (assay using endpoint titre ELISA).


Enrollment: 187
Study Start Date: May 2008
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: M01ZH09 Vaccine Candidate Cohort 1
Dose of 5.0 x 10^9 colony forming units (CFU) S. typhi (Ty2 aroC‾ssaV‾) ZH9 or placebo, administered as a single, oral dose
Biological: Dose of 5.0 x 10^9 CFU (Cohort 1)
S. typhi (Ty2 aroC‾ssaV‾) ZH9 live attenuated typhoid vaccine, single dose, oral administration
Other: Placebo (Cohorts 1-4 pooled)
Excipients only, single dose, oral administration
Experimental: M01ZH09 Vaccine Candidate Cohort 2
Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC‾ssaV‾) ZH9 or placebo, administered as a single, oral dose
Biological: Dose of 7.5 x 10^9 CFU (Cohort 2)
S. typhi (Ty2 aroC‾ssaV‾) ZH9 live attenuated typhoid vaccine, single dose, oral administration
Other: Placebo (Cohorts 1-4 pooled)
Excipients only, single dose, oral administration
Experimental: M01ZH09 Vaccine Candidate Cohort 3
Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC‾ssaV‾) ZH9 or placebo, administered as a single, oral dose
Biological: Dose of 1.1 x 10^10 CFU (Cohort 3)
S. typhi (Ty2 aroC‾ssaV‾) ZH9 live attenuated typhoid vaccine, single dose, oral administration
Other: Placebo (Cohorts 1-4 pooled)
Excipients only, single dose, oral administration
Experimental: M01ZH09 Vaccine Candidate Cohort 4
Dose of of 1.7 x 10^10 CFU S. typhi (Ty2 aroC‾ssaV‾) ZH9 or placebo, administered as a single, oral dose
Biological: Dose of of 1.7 x 10^10 CFU (Cohort 4)
S. typhi (Ty2 aroC‾ssaV‾) ZH9 live attenuated typhoid vaccine, single dose, oral administration
Other: Placebo (Cohorts 1-4 pooled)
Excipients only, single dose, oral administration

Detailed Description:
This was a randomised, double-blind, placebo-controlled, single dose, dose escalation study with 4 dosing cohorts. Within each cohort, 45 evaluable subjects were planned (36 subjects receiving M01ZH09, 9 receiving placebo).
  Eligibility

Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • healthy adult subjects aged 18 to 50 years inclusive, who are able and willing to give informed consent, following a detailed explanation of participation in protocol
  • available for the duration of the study and available for scheduled and potential additional visits

Exclusion Criteria:

  • women who are pregnant, breast-feeding or of childbearing potential and unwilling to use a reliable method of contraception throughout the study period
  • history of anaphylactic shock following vaccination by any route have phenylketonuria
  • hypersensitivity to any component of the vaccine or are hypersensitive to two of the following antibiotics: ciprofloxacin, azithromycin, ampicillin, trimethoprim sulfamethoxazole
  • received antibiotic medication within 14 days prior to dosing
  • received any vaccine within 4 weeks prior to dosing or plan to receive a vaccine within 4 weeks after dosing
  • received any vaccine against Salmonella typhi (licensed or investigational) or ever suffered from typhoid fever
  • subjects who test positive for hepatitis B, hepatitis C, HIV or human leucocyte antigen B-27
  • known or suspected history of liver or active gall bladder disease, ongoing gastro-intestinal disease or abnormality
  • commercial food handlers or health care workers with direct contact with high risk patients or who have household contacts with immuno-compromised individuals, pregnant women or children less than 2 years of age
  • subjects who have a clinically significant amount of protein or haemoglobin in their urine or abnormality of their haematology or serum biochemistry parameters
  • impairment of immune function or those receiving or have received cytotoxic drugs in the 6 months prior to study entry
  • subjects who use antacids, proton pump inhibitors or H2 blockers on a regular basis or have consumed proton pump inhibitors or H2 blockers within 24 hours prior to dosing
  • acute infections (including fever of 37.5 degrees Celsius or greater) on the day of dosing.
  • subjects with chronic disease (e.g Crohn's disease, inflammatory bowel disease, diabetes) who cannot withstand a 3 hour fast
  • substance abuse or a history of substance abuse that might interfere with participation in the study
  • body mass index (BMI) is less than 19 or greater than 34 kg per m2
  • clinically significant medical condition that precludes participation in the study
  • subjects who have participated in an interventional clinical trial within 60 days of dosing
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00679172

Locations
United States, Florida
Miami Research Associates
South Miami, Florida, United States, 33143
United States, Maryland
John Hopkins Bloomberg School of Public Health
Baltimore, Maryland, United States, 21205
United States, Vermont
Unit of Infectious Diseases, University of Vermont College of Medicine
Burlington, Vermont, United States, 05405
Sponsors and Collaborators
Emergent BioSolutions
Investigators
Study Director: Stephen Lockhart, DM Emergent BioSolutions
  More Information

Publications:
Responsible Party: Emergent BioSolutions
ClinicalTrials.gov Identifier: NCT00679172     History of Changes
Other Study ID Numbers: MS01.13
Study First Received: May 14, 2008
Results First Received: May 2, 2017
Last Updated: June 6, 2017
Individual Participant Data  
Plan to Share IPD: No

Additional relevant MeSH terms:
Typhoid Fever
Salmonella Infections
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Vaccines
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on June 23, 2017