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

Study Overview
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Brief Summary
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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
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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).

Official Title
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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.

Conditions
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Typhoid

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: M01ZH09 Vaccine Candidate Cohort 1<br>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)<br>* S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration<br>Other: Placebo (Cohorts 1-4 pooled)<br>* Excipients only, single dose, oral administration<br>|
| Experimental: M01ZH09 Vaccine Candidate Cohort 2<br>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)<br>* S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration<br>Other: Placebo (Cohorts 1-4 pooled)<br>* Excipients only, single dose, oral administration<br>|
| Experimental: M01ZH09 Vaccine Candidate Cohort 3<br>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)<br>* S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration<br>Other: Placebo (Cohorts 1-4 pooled)<br>* Excipients only, single dose, oral administration<br>|
| Experimental: M01ZH09 Vaccine Candidate Cohort 4<br>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)<br>* S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration<br>Other: Placebo (Cohorts 1-4 pooled)<br>* Excipients only, single dose, oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Proportion of Subjects Reporting Suspected Unexpected Serious Adverse Reactions. | Number and proportion of subjects reporting suspected unexpected serious adverse reactions (SUSARs). | From start of dosing to 28 days post-dosing. | 
| 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. | From start of dosing to 14 days post-dosing. | 
| Number of Subjects Having Clinically Significant Changes in Laboratory Test Parameters. | Number of subjects having clinically significant changes in clinical laboratory test parameters. | From start of dosing to 28 days post-dosing. | 
| 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. | From start of dosing to 28 days post-dosing. | 
| 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. | From start of dosing to 28 days post-dosing. | 
| 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. | Beyond 7 days post-dosing through 14 days post-dosing (Cohorts 1-3) or through 21 days post-dosing (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). | From baseline (pre-dose) to Days 14 or 28 (IgG) or to Days 7 or 14 (IgA). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From baseline (pre-dose) to Days 7 or 14. | 
| 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. | From baseline (pre-dose) to Days 14 or 28. | 
| 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. | From baseline (pre-dose) to Days 7, 14, or 28. | 
| 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). | At Day 7 (IgA); and from baseline (pre-dose) to Day 28 (IgG). | 
| 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). | Day 7. | 
| 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). | From baseline (pre-dose) to Day 28. |