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

• Sponsor: Emergent BioSolutions (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00679172
• Collaborator: (none)
• Enrollment: 187
• Locations: 3
• Arms: 4
• Duration (Months): 7
• Patients Per Site: 62.3
• Patients Per Site Per Month: 8.9

Study Details

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.

Condition or Disease	Intervention/Treatment	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

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 187 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Triple (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.
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. Number and Proportion of Subjects Reporting Suspected Unexpected Serious Adverse Reactions. [From start of dosing to 28 days post-dosing.]

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

2. Number and Proportion of Subjects Experiencing Symptomatic Fever. [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.

3. Number of Subjects Having Clinically Significant Changes in Laboratory Test Parameters. [From start of dosing to 28 days post-dosing.]

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

4. Number of Subjects Reporting Treatment-related TEAEs. [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.

5. Number and Proportion of Subjects Experiencing Bacteraemia. [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.

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

7. 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). [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

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

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

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

4. 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. [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).

5. 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. [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).

6. 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. [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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Locations

	Site	City	State	Country	Postal Code
1	Miami Research Associates	South Miami	Florida	United States	33143
2	John Hopkins Bloomberg School of Public Health	Baltimore	Maryland	United States	21205
3	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Emergent BioSolutions
• ClinicalTrials.gov Identifier: NCT00679172
• Other Study ID Numbers: MS01.13
• First Posted: May 16, 2008
• Last Update Posted: Jun 7, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Typhoid Fever

Study Results

Participant Flow

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Period Title: Overall Study
STARTED	37	38	36	39	37
COMPLETED	36	37	35	38	37
NOT COMPLETED	1	1	1	1	0

Baseline Characteristics

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo	Total
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.	Total of all reporting groups
Overall Participants	37	38	36	39	37	187
Age (Count of Participants)
<=18 years	1 2.7%	0 0%	1 2.8%	1 2.6%	1 2.7%	4 2.1%
Between 18 and 65 years	36 97.3%	38 100%	35 97.2%	38 97.4%	36 97.3%	183 97.9%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.2 (10.13)	33.1 (10.00)	32.0 (9.99)	31.3 (9.21)	32.3 (10.01)	32.4 (9.79)
Sex: Female, Male (Count of Participants)
Female	18 48.6%	17 44.7%	19 52.8%	19 48.7%	21 56.8%	94 50.3%
Male	19 51.4%	21 55.3%	17 47.2%	20 51.3%	16 43.2%	93 49.7%
Region of Enrollment (participants) [Number]
United States	37 100%	38 100%	36 100%	39 100%	37 100%	187 100%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Safety Population: All subjects who received a dose of study medication.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%

2. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Safety Population: All subjects who received a dose of study medication.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Count of Participants [Participants]	1 2.7%	0 0%	1 2.8%	0 0%	0 0%

3. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Safety Population: All subjects who received a dose of study medication.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Alanine aminotransferase	1 2.7%	0 0%	0 0%	0 0%	0 0%
Creatinine	0 0%	0 0%	0 0%	0 0%	0 0%
Eosinophils	0 0%	0 0%	0 0%	0 0%	0 0%
Haematocrit	0 0%	0 0%	0 0%	1 2.6%	0 0%
Haemoglobin	0 0%	0 0%	0 0%	1 2.6%	0 0%
Lymphocytes	0 0%	0 0%	0 0%	0 0%	1 2.7%
Neutrophils	0 0%	0 0%	0 0%	0 0%	1 2.7%
Platelet Count	0 0%	0 0%	0 0%	0 0%	0 0%
Red Blood Cell Count	0 0%	0 0%	0 0%	1 2.6%	0 0%
White Blood Cell Count	0 0%	0 0%	0 0%	0 0%	0 0%

4. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Safety Population: All subjects who received a dose of study medication.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Subjects with possibly related TEAEs	19 51.4%	12 31.6%	18 50%	10 25.6%	15 40.5%
Subjects with probably related TEAEs	7 18.9%	10 26.3%	6 16.7%	19 48.7%	9 24.3%

5. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Safety Population: All subjects who received a dose of study medication.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%

6. Primary Outcome

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).

Outcome Measure Data

Analysis Population Description

Safety Population: All subjects who received a dose of study medication.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Day 9	1 2.7%	0 0%	1 2.8%	1 2.6%	0 0%
Day 11	0 0%	1 2.6%	0 0%	2 5.1%	0 0%
Day 14	0 0%	0 0%	0 0%	1 2.6%	0 0%
Day 17	2 5.4%	0 0%
Day 19	0 0%	0 0%
Day 21	0 0%	0 0%

7. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population: all subjects who received study medication and had any postbaseline immunogenicity data available up to and including Day 28.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC- ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Count of Participants [Participants]	32 86.5%	35 92.1%	32 88.9%	38 97.4%	6 16.2%

8. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

ITT Population: all subjects who received study medication and had any postbaseline immunogenicity data available up to and including Day 28.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Count of Participants [Participants]	31 83.8%	35 92.1%	30 83.3%	38 97.4%	1 2.7%

9. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

ITT Population: all subjects who received study medication and had any postbaseline immunogenicity data available up to and including Day 28.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Count of Participants [Participants]	23 62.2%	30 78.9%	31 86.1%	33 84.6%	5 13.5%

10. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

ITT Population: all subjects who received study medication and had any postbaseline immunogenicity data available up to and including Day 14.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
Measure Participants	37	38	36	39	37
Count of Participants [Participants]	25 67.6%	30 78.9%	31 86.1%	33 84.6%	7 18.9%

11. Secondary Outcome

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 Antibody Secreting Cells (ASCs) Secreting IgA and/or Fold Change in IgG.
Description	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).
Time Frame	At Day 7 (IgA); and from baseline (pre-dose) to Day 28 (IgG).

Outcome Measure Data

Analysis Population Description

ITT Population (Cohort 2): all subjects who received study medication and had any postbaseline immunogenicity data available up to and including Day 28.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 2	Placebo - Cohort 2
Arm/Group Description	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only - Cohort 2
Measure Participants	38	9
Count of Participants [Participants]	36 97.3%	0 0%

12. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

ITT Population (Cohort 2): all subjects who received study medication and had any postbaseline immunogenicity data available up to and including Day 28.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 2	Placebo - Cohort 2
Arm/Group Description	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only - Cohort 2
Measure Participants	38	9
Count of Participants [Participants]	35 94.6%	0 0%

13. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

ITT Population (Cohort 2): all subjects who received study medication and had any postbaseline immunogenicity data available up to and including Day 28.

Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 2	Placebo - Cohort 2
Arm/Group Description	Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	Placebo comparator comprised of excipients only - Cohort 2
Measure Participants	38	9
Count of Participants [Participants]	14 37.8%	0 0%

Adverse Events

Time Frame	Up to Day 28.
Adverse Event Reporting Description	Treatment-emergent adverse events (TEAEs) are defined as those adverse events which occurred postdose or which were present predose and became worse postdose. The proportions of subjects reported TEAEs and SAEs were pre-defined safety outcome variables.
Arm/Group Title	M01ZH09 Vaccine Candidate Cohort 1		M01ZH09 Vaccine Candidate Cohort 2		M01ZH09 Vaccine Candidate Cohort 3		M01ZH09 Vaccine Candidate Cohort 4		Pooled Placebo
Arm/Group Description	Dose of 5.0 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.		Dose of 7.5 x 10^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.		Dose of 1.1 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.		Dose of 1.7 x 10^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.		Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.
All Cause Mortality
	M01ZH09 Vaccine Candidate Cohort 1		M01ZH09 Vaccine Candidate Cohort 2		M01ZH09 Vaccine Candidate Cohort 3		M01ZH09 Vaccine Candidate Cohort 4		Pooled Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/38 (0%)		0/36 (0%)		0/39 (0%)		0/37 (0%)
Serious Adverse Events
	M01ZH09 Vaccine Candidate Cohort 1		M01ZH09 Vaccine Candidate Cohort 2		M01ZH09 Vaccine Candidate Cohort 3		M01ZH09 Vaccine Candidate Cohort 4		Pooled Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/38 (0%)		0/36 (0%)		0/39 (0%)		0/37 (0%)
Other (Not Including Serious) Adverse Events
	M01ZH09 Vaccine Candidate Cohort 1		M01ZH09 Vaccine Candidate Cohort 2		M01ZH09 Vaccine Candidate Cohort 3		M01ZH09 Vaccine Candidate Cohort 4		Pooled Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/37 (73%)		26/38 (68.4%)		30/36 (83.3%)		33/39 (84.6%)		31/37 (83.8%)
Blood and lymphatic system disorders
Anaemia	0/37 (0%)		0/38 (0%)		0/36 (0%)		0/39 (0%)		2/37 (5.4%)
Gastrointestinal disorders
Abdominal pain	11/37 (29.7%)		12/38 (31.6%)		7/36 (19.4%)		12/39 (30.8%)		8/37 (21.6%)
Constipation	7/37 (18.9%)		4/38 (10.5%)		1/36 (2.8%)		5/39 (12.8%)		8/37 (21.6%)
Diarrhoea	5/37 (13.5%)		10/38 (26.3%)		6/36 (16.7%)		9/39 (23.1%)		10/37 (27%)
Flatulence	17/37 (45.9%)		15/38 (39.5%)		10/36 (27.8%)		10/39 (25.6%)		14/37 (37.8%)
Nausea	9/37 (24.3%)		6/38 (15.8%)		3/36 (8.3%)		10/39 (25.6%)		5/37 (13.5%)
Dyspepsia	1/37 (2.7%)		1/38 (2.6%)		2/36 (5.6%)		0/39 (0%)		0/37 (0%)
General disorders
Asthenia	8/37 (21.6%)		13/38 (34.2%)		6/36 (16.7%)		7/39 (17.9%)		8/37 (21.6%)
Chills	2/37 (5.4%)		0/38 (0%)		2/36 (5.6%)		7/39 (17.9%)		1/37 (2.7%)
Fatigue	0/37 (0%)		0/38 (0%)		0/36 (0%)		3/39 (7.7%)		1/37 (2.7%)
Infections and infestations
Upper respiratory tract infection	0/37 (0%)		1/38 (2.6%)		2/36 (5.6%)		4/39 (10.3%)		3/37 (8.1%)
Investigations
Culture stool positive	1/37 (2.7%)		1/38 (2.6%)		1/36 (2.8%)		3/39 (7.7%)		0/37 (0%)
Metabolism and nutrition disorders
Anorexia	3/37 (8.1%)		8/38 (21.1%)		1/36 (2.8%)		4/39 (10.3%)		7/37 (18.9%)
Musculoskeletal and connective tissue disorders
Myalgia	4/37 (10.8%)		6/38 (15.8%)		3/36 (8.3%)		7/39 (17.9%)		7/37 (18.9%)
Arthralgia	2/37 (5.4%)		1/38 (2.6%)		1/36 (2.8%)		1/39 (2.6%)		1/37 (2.7%)
Back pain	2/37 (5.4%)		0/38 (0%)		0/36 (0%)		2/39 (5.1%)		2/37 (5.4%)
Neck pain	0/37 (0%)		0/38 (0%)		3/36 (8.3%)		0/39 (0%)		1/37 (2.7%)
Muscle spasms	0/37 (0%)		0/38 (0%)		0/36 (0%)		1/39 (2.6%)		2/37 (5.4%)
Nervous system disorders
Headache	16/37 (43.2%)		5/38 (13.2%)		9/36 (25%)		15/39 (38.5%)		13/37 (35.1%)
Dizziness	0/37 (0%)		1/38 (2.6%)		2/36 (5.6%)		1/39 (2.6%)		1/37 (2.7%)
Reproductive system and breast disorders
Dysmenorrhoea	0/18 (0%)		1/17 (5.9%)		2/19 (10.5%)		1/19 (5.3%)		1/21 (4.8%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	2/37 (5.4%)		1/38 (2.6%)		0/36 (0%)		2/39 (5.1%)		2/37 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Any proposed publication was subject to review conditions and timelines agreed between Emergent Product Development UK Ltd and the site Principal Investigator and detailed in the agreements with these parties prior to the start of the study.