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

Primary Purpose

Typhoid

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Dose of 5.0 x 10^9 CFU (Cohort 1)

Dose of 7.5 x 10^9 CFU (Cohort 2)

Dose of 1.1 x 10^10 CFU (Cohort 3)

Dose of of 1.7 x 10^10 CFU (Cohort 4)

Placebo (Cohorts 1-4 pooled)

About this trial

This is an interventional prevention trial for Typhoid

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Miami Research Associates
John Hopkins Bloomberg School of Public Health
Unit of Infectious Diseases, University of Vermont College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

M01ZH09 Vaccine Candidate Cohort 1

M01ZH09 Vaccine Candidate Cohort 2

M01ZH09 Vaccine Candidate Cohort 3

M01ZH09 Vaccine Candidate Cohort 4

Arm Description

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

Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9 or placebo, administered as a single, oral dose

Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9 or placebo, administered as a single, oral dose

Dose of of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9 or placebo, administered as a single, oral dose

Outcomes

Primary Outcome Measures

Number and Proportion of Subjects Reporting Suspected Unexpected Serious Adverse Reactions.

Number and proportion of subjects reporting suspected unexpected serious adverse reactions (SUSARs).

Number and Proportion of Subjects Experiencing Symptomatic Fever.

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.

Number of subjects having clinically significant changes in clinical laboratory test parameters.

Number of Subjects Reporting Treatment-related TEAEs.

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.

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.

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).

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.

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.

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.

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.

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.

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.

Number and proportion of subjects with 4-fold increase for serum IgG on Day 28 compared to baseline (assay using endpoint titre ELISA).

Full Information

NCT ID

NCT00679172

First Posted

May 14, 2008

Last Updated

June 6, 2017

Sponsor

Emergent BioSolutions

1. Study Identification

Unique Protocol Identification Number

NCT00679172

Brief Title

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

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.

Study Type

Interventional

2. Study Status

Record Verification Date

June 2017

Overall Recruitment Status

Completed

Study Start Date

May 2008 (undefined)

Primary Completion Date

December 2008 (Actual)

Study Completion Date

December 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Emergent BioSolutions

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Typhoid

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Sequential Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

187 (Actual)

8. Arms, Groups, and Interventions

Arm Title

M01ZH09 Vaccine Candidate Cohort 1

Arm Type

Experimental

Arm Description

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

Arm Title

M01ZH09 Vaccine Candidate Cohort 2

Arm Type

Experimental

Arm Description

Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9 or placebo, administered as a single, oral dose

Arm Title

M01ZH09 Vaccine Candidate Cohort 3

Arm Type

Experimental

Arm Description

Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9 or placebo, administered as a single, oral dose

Arm Title

M01ZH09 Vaccine Candidate Cohort 4

Arm Type

Experimental

Arm Description

Dose of of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9 or placebo, administered as a single, oral dose

Intervention Type

Biological

Intervention Name(s)

Dose of 5.0 x 10^9 CFU (Cohort 1)

Intervention Description

S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration

Intervention Type

Biological

Intervention Name(s)

Dose of 7.5 x 10^9 CFU (Cohort 2)

Intervention Description

S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration

Intervention Type

Biological

Intervention Name(s)

Dose of 1.1 x 10^10 CFU (Cohort 3)

Intervention Description

S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration

Intervention Type

Biological

Intervention Name(s)

Dose of of 1.7 x 10^10 CFU (Cohort 4)

Intervention Description

S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration

Intervention Type

Other

Intervention Name(s)

Placebo (Cohorts 1-4 pooled)

Intervention Description

Excipients only, single dose, oral administration

Primary Outcome Measure Information:

Title

Number and Proportion of Subjects Reporting Suspected Unexpected Serious Adverse Reactions.

Description

Number and proportion of subjects reporting suspected unexpected serious adverse reactions (SUSARs).

Time Frame

From start of dosing to 28 days post-dosing.

Title

Number and Proportion of Subjects Experiencing Symptomatic Fever.

Description

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.

Time Frame

From start of dosing to 14 days post-dosing.

Title

Number of Subjects Having Clinically Significant Changes in Laboratory Test Parameters.

Description

Number of subjects having clinically significant changes in clinical laboratory test parameters.

Time Frame

From start of dosing to 28 days post-dosing.

Title

Number of Subjects Reporting Treatment-related TEAEs.

Description

Number of subjects having TEAEs considered by the principal investigator to be "possibly" or "probably" related to treatment.

Time Frame

From start of dosing to 28 days post-dosing.

Title

Number and Proportion of Subjects Experiencing Bacteraemia.

Description

Number and proportion of subjects experiencing a proven bacteraemia attributed to the vaccine strain S. typhi (Ty2 aroC-ssaV-) ZH9.

Time Frame

From start of dosing to 28 days post-dosing.

Title

Number of Subjects Having Shedding in Stool of Salmonella Typhi (S. Typhi) (Ty2 aroC-ssaV-) ZH9.

Description

Number of subjects having shedding in stool of S. typhi (Ty2 aroC-ssaV-) ZH9. Subjects were evaluated beyond Day 14 only in Cohort 4.

Time Frame

Beyond 7 days post-dosing through 14 days post-dosing (Cohorts 1-3) or through 21 days post-dosing (Cohort 4).

Title

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).

Description

Time Frame

From baseline (pre-dose) to Days 14 or 28 (IgG) or to Days 7 or 14 (IgA).

Secondary Outcome Measure Information:

Title

Number and Proportion of Subjects Developing an Immune Response as Determined by the Level of IgA Antibodies for S. Typhi LPS.

Description

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.

Time Frame

From baseline (pre-dose) to Days 7 or 14.

Title

Number and Proportion of Subjects Developing an Immune Response as Determined by the Level of IgG Antibodies for S. Typhi LPS.

Description

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.

Time Frame

From baseline (pre-dose) to Days 14 or 28.

Title

Number and Proportion of Subjects Developing an Immune Response as Determined by the Level of IgG Antibodies for S. Typhi LPS.

Description

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.

Time Frame

From baseline (pre-dose) to Days 7, 14, or 28.

Title

Description

Time Frame

At Day 7 (IgA); and from baseline (pre-dose) to Day 28 (IgG).

Title

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.

Description

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).

Time Frame

Day 7.

Title

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.

Description

Number and proportion of subjects with 4-fold increase for serum IgG on Day 28 compared to baseline (assay using endpoint titre ELISA).

Time Frame

From baseline (pre-dose) to Day 28.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stephen Lockhart, DM

Organizational Affiliation

Emergent BioSolutions

Official's Role

Study Director

Facility Information:

Facility Name

Miami Research Associates

City

South Miami

State/Province

Florida

ZIP/Postal Code

33143

Country

United States

Facility Name

John Hopkins Bloomberg School of Public Health

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21205

Country

United States

Facility Name

Unit of Infectious Diseases, University of Vermont College of Medicine

City

Burlington

State/Province

Vermont

ZIP/Postal Code

05405

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

20188175

Citation

Lyon CE, Sadigh KS, Carmolli MP, Harro C, Sheldon E, Lindow JC, Larsson CJ, Martinez T, Feller A, Ventrone CH, Sack DA, DeNearing B, Fingar A, Pierce K, Dill EA, Schwartz HI, Beardsworth EE, Kilonzo B, May JP, Lam W, Upton A, Budhram R, Kirkpatrick BD. In a randomized, double-blinded, placebo-controlled trial, the single oral dose typhoid vaccine, M01ZH09, is safe and immunogenic at doses up to 1.7 x 10(10) colony-forming units. Vaccine. 2010 Apr 30;28(20):3602-8. doi: 10.1016/j.vaccine.2010.02.017. Epub 2010 Feb 24.

Results Reference

result

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

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