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

Typhoid Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00679172
• Other study ID #: MS01.13
• Status: Completed
• Phase: Phase 2
• Start date: May 2008
• Est. completion date: December 2008

Study information

• Verified date: March 2024
• Source: Emergent BioSolutions
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 187
• Est. completion date: December 2008
• Est. primary completion date: December 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Typhoid
• Typhoid Fever

Intervention

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
• Dose of 7.5 x 10^9 CFU (Cohort 2)
S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration
• Dose of 1.1 x 10^10 CFU (Cohort 3)
S. typhi (Ty2 aroC-ssaV-) ZH9 live attenuated typhoid vaccine, single dose, oral administration
• 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

Locations

Country	Name	City	State
United States	John Hopkins Bloomberg School of Public Health	Baltimore	Maryland
United States	Unit of Infectious Diseases, University of Vermont College of Medicine	Burlington	Vermont
United States	Miami Research Associates	South Miami	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Emergent BioSolutions

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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.
Primary	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.
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.	From start of dosing to 28 days post-dosing.
Primary	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).
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).	From baseline (pre-dose) to Days 14 or 28 (IgG) or to Days 7 or 14 (IgA).
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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).
Secondary	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.
Secondary	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.