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

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.

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00679172

Enrollment

187

Registered

2008-05-16

Start date

2008-05-31

Completion date

2008-12-31

Last updated

2024-04-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Typhoid

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).

Interventions

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

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

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

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

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

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

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

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

OTHERPlacebo (Cohorts 1-4 pooled)

Excipients only, single dose, oral administration

Study design

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

PREVENTION

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 50 Years

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

Design outcomes

Primary

Measure	Time frame	Description
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).
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.
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.
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.
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.
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.
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).

Secondary

Measure	Time frame	Description
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.
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).
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).
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).
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
M01ZH09 Vaccine Candidate Cohort 1 Dose of 5.0 x 10\^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	37
M01ZH09 Vaccine Candidate Cohort 2 Dose of 7.5 x 10\^9 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	38
M01ZH09 Vaccine Candidate Cohort 3 Dose of 1.1 x 10\^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	36
M01ZH09 Vaccine Candidate Cohort 4 Dose of 1.7 x 10\^10 CFU S. typhi (Ty2 aroC-ssaV-) ZH9.	39
Pooled Placebo Placebo comparator comprised of excipients only, pooled across Cohorts 1-4.	37
Total	187

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Non-compliance	1	1	0	1	0
Overall Study	Other not specified	0	0	1	0	0

Baseline characteristics

Characteristic	M01ZH09 Vaccine Candidate Cohort 2	M01ZH09 Vaccine Candidate Cohort 3	M01ZH09 Vaccine Candidate Cohort 4	M01ZH09 Vaccine Candidate Cohort 1	Pooled Placebo	Total
Age, Categorical <=18 years	0 Participants	1 Participants	1 Participants	1 Participants	1 Participants	4 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	38 Participants	35 Participants	38 Participants	36 Participants	36 Participants	183 Participants
Age, Continuous	33.1 years STANDARD_DEVIATION 10	32.0 years STANDARD_DEVIATION 9.99	31.3 years STANDARD_DEVIATION 9.21	33.2 years STANDARD_DEVIATION 10.13	32.3 years STANDARD_DEVIATION 10.01	32.4 years STANDARD_DEVIATION 9.79
Region of Enrollment United States	38 participants	36 participants	39 participants	37 participants	37 participants	187 participants
Sex: Female, Male Female	17 Participants	19 Participants	19 Participants	18 Participants	21 Participants	94 Participants
Sex: Female, Male Male	21 Participants	17 Participants	20 Participants	19 Participants	16 Participants	93 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 37	0 / 38	0 / 36	0 / 39	0 / 37
other Total, other adverse events	27 / 37	26 / 38	30 / 36	33 / 39	31 / 37
serious Total, serious adverse events	0 / 37	0 / 38	0 / 36	0 / 39	0 / 37

Outcome results

Primary

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).

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

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
M01ZH09 Vaccine Candidate Cohort 1	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).	32 Participants
M01ZH09 Vaccine Candidate Cohort 2	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).	35 Participants
M01ZH09 Vaccine Candidate Cohort 3	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).	32 Participants
M01ZH09 Vaccine Candidate 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).	38 Participants
Pooled Placebo	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).	6 Participants

Primary

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.

Time frame: From start of dosing to 28 days post-dosing.