search
Back to results

Understanding Typhoid Disease After Vaccination

Primary Purpose

Typhoid Fever, Enteric Fever, Typhoid

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Vaccine placebo (excipients only)
Ty21a
M10ZH09 vaccine
Sponsored by
University of Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Typhoid Fever focused on measuring typhoid vaccine M01ZH09, Ty21a typhoid vaccine

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion criteria:

  • Male or female aged 18 - 60 years inclusive and in good health.
  • Have an abdominal ultrasound scan result documented demonstrating no evidence of gallbladder pathology.
  • Willing to allow their general practitioner and/or hospital consultant (if relevant) and the Health Protection Unit to be notified of participation in the study.
  • Agree to refrain from blood donation in the future if diagnosed with typhoid fever.
  • Be willing to have 24-hour contact with study staff during the four weeks post-challenge.

Exclusion Criteria:

  • Have previously received any typhoid vaccine, been resident in a typhoid endemic country for over 6 months, been diagnosed with probable or confirmed typhoid infection or been challenged with Salmonella Typhi or enrolled in a typhoid challenge study.
  • Have any known or suspected impairment or alteration of immune function.
  • History of significant cardiovascular disease.
  • History of significant respiratory disease.
  • History of significant endocrine disorder.
  • History of significant renal or bladder disease.
  • History of biliary tract disease.
  • History of significant gastrointestinal disease.
  • History of significant neurological disease.
  • History of significant metabolic disease.
  • History of significant haematological diagnosis.
  • History of psychiatric illness requiring hospitalisation, current known or suspected drug or alcohol misuse.
  • History of significant infectious disease.
  • History of non-benign cancer.
  • Presence of any implants or prostheses.
  • Hypersensitivity to any component of the vaccine or are hypersensitive to two or more of the following antibiotics: ciprofloxacin, azithromycin, ampicillin, trimethoprim sulfamethoxazole.
  • Female participant who is pregnant, lactating or who is unwilling to ensure that they or their partner use effective contraception one month prior to vaccination and continue to do so until two negative stool samples obtained a week apart, a minimum of 1 week after completion of antibiotic treatment have been obtained.
  • Current occupation involving: clinical or social work with direct contact with young children (defined as those attending pre-school groups, nursery or aged less than 2 years); highly susceptible patients or persons in whom typhoid infection would have particularly serious consequences (i.e. those who are immunocompromised or debilitated); care work involving the elderly.
  • Current occupation as a commercial food handler involving the preparation or serving of unwrapped foods not subjected to further heating.
  • Household contact with a young child (defined as above).
  • Household/close contact who is immunocompromised.
  • Scheduled elective surgery or other procedures requiring general anaesthesia during the vaccine/challenge period, at time of enrolment.
  • Participants who have taken part in other research involving an investigational product (IMP) within the 30 days prior to enrolment.
  • Have received blood, blood products and/or plasma derivatives including parenteral immunoglobulin preparations in the previous 3 months
  • Any other significant disease or disorder which, in the opinion of the investigator, may put the participants at risk because of participation in the study, may influence the result of the study, or affect the participant's ability to participate in the study.

Sites / Locations

  • Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Other

Arm Label

M01ZH09 vaccine

Vaccine placebo

Ty21a vaccine

Arm Description

Positive control

Outcomes

Primary Outcome Measures

Diagnosis of typhoid fever
Typhoid fever defined as development of Gram negative bacteraemia after day 5 or temperature over 38C persisting for 12 hours or more. Typhoid challenge defined as ingestion of virulent S. Typhi (Quailes strain).

Secondary Outcome Measures

Full Information

First Posted
July 28, 2011
Last Updated
May 3, 2023
Sponsor
University of Oxford
Collaborators
Wellcome Trust, Imperial College London, University of Maryland
search

1. Study Identification

Unique Protocol Identification Number
NCT01405521
Brief Title
Understanding Typhoid Disease After Vaccination
Official Title
Understanding Typhoid Disease After Vaccination: a Single Centre, Randomised, Doubleblind, Placebo Controlled Study to Evaluate M01ZH09 in a Healthy Adult Challenge Model, Using Ty21a Vaccine as a Positive Control.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
October 7, 2011 (Actual)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
May 6, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford
Collaborators
Wellcome Trust, Imperial College London, University of Maryland

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Using an established model of human typhoid infection, whereby healthy adults are deliberately infected with typhoid-causing bacteria, the investigators will determine how effective a new oral typhoid vaccine (M01ZH09) is in preventing infection. A previously licensed oral typhoid vaccine (Ty21a) will be used to make sure the challenge model used works properly.
Detailed Description
Typhoid is a serious infection killing up to 600,000 people every year; it is a frequent cause of fever and hospital admission in areas where disease is common. As the infection is restricted to humans, it should be possible to eliminate typhoid; better vaccines and ways of confirming infection are required in order for this to succeed. We propose to use a recently established human typhoid challenge model in order to evaluate a novel oral vaccine candidate and to develop new methods for diagnosing typhoid. Although there are vaccines available to prevent typhoid, they offer little protection to populations where typhoid predominates, especially young children. Currently, the effectiveness of vaccines against typhoid cannot be predicted, as measures of protection against typhoid are unknown. As a result, implementation of vaccine programmes in disease endemic regions currently requires large and expensive trials in each new population, significantly delaying programmatic implementation. We will use a typhoid challenge model to achieve our goal of accelerating the introduction of more effective vaccines into populations with a high burden of disease. Healthy adults will be vaccinated with either a novel oral typhoid vaccine or vaccine-placebo prior to being infected with the bacteria causing typhoid. This will allow us to measure the effectiveness of the vaccine and to identify components of the immune response important in producing protection against infection. Current methods for confirming typhoid infection are slow and insensitive, particularly in endemic regions where the cost of laboratory equipment is prohibitive. In this project, we will also explore ways to diagnose typhoid, with the aim of developing tests that are quick, reliable and are be cost-effective in resource-poor settings. This would improve individual patient management, and allow accurate measurement of disease burden, which is vital to improve the efforts of vaccine programmes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Typhoid Fever, Enteric Fever, Typhoid
Keywords
typhoid vaccine M01ZH09, Ty21a typhoid vaccine

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
99 (Actual)

8. Arms, Groups, and Interventions

Arm Title
M01ZH09 vaccine
Arm Type
Experimental
Arm Title
Vaccine placebo
Arm Type
Placebo Comparator
Arm Title
Ty21a vaccine
Arm Type
Other
Arm Description
Positive control
Intervention Type
Biological
Intervention Name(s)
Vaccine placebo (excipients only)
Intervention Description
single oral dose,
Intervention Type
Biological
Intervention Name(s)
Ty21a
Other Intervention Name(s)
Vivotif
Intervention Description
3 oral doses, alternate days
Intervention Type
Biological
Intervention Name(s)
M10ZH09 vaccine
Other Intervention Name(s)
Typhella
Intervention Description
single oral dose
Primary Outcome Measure Information:
Title
Diagnosis of typhoid fever
Description
Typhoid fever defined as development of Gram negative bacteraemia after day 5 or temperature over 38C persisting for 12 hours or more. Typhoid challenge defined as ingestion of virulent S. Typhi (Quailes strain).
Time Frame
2 weeks after typhoid challenge

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion criteria: Male or female aged 18 - 60 years inclusive and in good health. Have an abdominal ultrasound scan result documented demonstrating no evidence of gallbladder pathology. Willing to allow their general practitioner and/or hospital consultant (if relevant) and the Health Protection Unit to be notified of participation in the study. Agree to refrain from blood donation in the future if diagnosed with typhoid fever. Be willing to have 24-hour contact with study staff during the four weeks post-challenge. Exclusion Criteria: Have previously received any typhoid vaccine, been resident in a typhoid endemic country for over 6 months, been diagnosed with probable or confirmed typhoid infection or been challenged with Salmonella Typhi or enrolled in a typhoid challenge study. Have any known or suspected impairment or alteration of immune function. History of significant cardiovascular disease. History of significant respiratory disease. History of significant endocrine disorder. History of significant renal or bladder disease. History of biliary tract disease. History of significant gastrointestinal disease. History of significant neurological disease. History of significant metabolic disease. History of significant haematological diagnosis. History of psychiatric illness requiring hospitalisation, current known or suspected drug or alcohol misuse. History of significant infectious disease. History of non-benign cancer. Presence of any implants or prostheses. Hypersensitivity to any component of the vaccine or are hypersensitive to two or more of the following antibiotics: ciprofloxacin, azithromycin, ampicillin, trimethoprim sulfamethoxazole. Female participant who is pregnant, lactating or who is unwilling to ensure that they or their partner use effective contraception one month prior to vaccination and continue to do so until two negative stool samples obtained a week apart, a minimum of 1 week after completion of antibiotic treatment have been obtained. Current occupation involving: clinical or social work with direct contact with young children (defined as those attending pre-school groups, nursery or aged less than 2 years); highly susceptible patients or persons in whom typhoid infection would have particularly serious consequences (i.e. those who are immunocompromised or debilitated); care work involving the elderly. Current occupation as a commercial food handler involving the preparation or serving of unwrapped foods not subjected to further heating. Household contact with a young child (defined as above). Household/close contact who is immunocompromised. Scheduled elective surgery or other procedures requiring general anaesthesia during the vaccine/challenge period, at time of enrolment. Participants who have taken part in other research involving an investigational product (IMP) within the 30 days prior to enrolment. Have received blood, blood products and/or plasma derivatives including parenteral immunoglobulin preparations in the previous 3 months Any other significant disease or disorder which, in the opinion of the investigator, may put the participants at risk because of participation in the study, may influence the result of the study, or affect the participant's ability to participate in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew J Pollard
Organizational Affiliation
Oxford Vaccine Group, Department of Paediatrics, University of Oxford
Official's Role
Principal Investigator
Facility Information:
Facility Name
Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine
City
Oxford
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
30252031
Citation
Gibani MM, Voysey M, Jin C, Jones C, Thomaides-Brears H, Jones E, Baker P, Morgan M, Simmons A, Gordon MA, Cerundolo V, Pitzer VE, Angus B, Levine MM, Darton TC, Pollard AJ. The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies. Clin Infect Dis. 2019 Apr 8;68(8):1265-1273. doi: 10.1093/cid/ciy670.
Results Reference
background
PubMed Identifier
26394303
Citation
Darton TC, Blohmke CJ, Giannoulatou E, Waddington CS, Jones C, Sturges P, Webster C, Drakesmith H, Pollard AJ, Armitage AE. Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans. PLoS Negl Trop Dis. 2015 Sep 22;9(9):e0004029. doi: 10.1371/journal.pntd.0004029. eCollection 2015 Sep.
Results Reference
background
PubMed Identifier
29387052
Citation
Juel HB, Thomaides-Brears HB, Darton TC, Jones C, Jones E, Shrestha S, Sie R, Eustace A, Galal U, Kurupati P, Van TT, Thieu NTV, Baker S, Blohmke CJ, Pollard AJ. Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model. Front Immunol. 2018 Jan 17;8:1916. doi: 10.3389/fimmu.2017.01916. eCollection 2017.
Results Reference
background
PubMed Identifier
29075261
Citation
Blohmke CJ, Hill J, Darton TC, Carvalho-Burger M, Eustace A, Jones C, Schreiber F, Goodier MR, Dougan G, Nakaya HI, Pollard AJ. Induction of Cell Cycle and NK Cell Responses by Live-Attenuated Oral Vaccines against Typhoid Fever. Front Immunol. 2017 Oct 12;8:1276. doi: 10.3389/fimmu.2017.01276. eCollection 2017.
Results Reference
background
PubMed Identifier
35254093
Citation
Barton A, Hill J, Bibi S, Chen L, Jones C, Jones E, Camara S, Shrestha S, Jin C, Gibani MM, Dobinson H, Waddington C, Darton TC, Blohmke CJ, Pollard AJ. Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers. Infect Immun. 2022 Apr 21;90(4):e0038921. doi: 10.1128/iai.00389-21. Epub 2022 Mar 7.
Results Reference
background
PubMed Identifier
28970824
Citation
Darton TC, Baker S, Randall A, Dongol S, Karkey A, Voysey M, Carter MJ, Jones C, Trappl K, Pablo J, Hung C, Teng A, Shandling A, Le T, Walker C, Molina D, Andrews J, Arjyal A, Basnyat B, Pollard AJ, Blohmke CJ. Identification of Novel Serodiagnostic Signatures of Typhoid Fever Using a Salmonella Proteome Array. Front Microbiol. 2017 Sep 19;8:1794. doi: 10.3389/fmicb.2017.01794. eCollection 2017.
Results Reference
background
PubMed Identifier
29109704
Citation
Darton TC, Jones C, Dongol S, Voysey M, Blohmke CJ, Shrestha R, Karkey A, Shakya M, Arjyal A, Waddington CS, Gibani M, Carter MJ, Basnyat B, Baker S, Pollard AJ. Assessment and Translation of the Antibody-in-Lymphocyte Supernatant (ALS) Assay to Improve the Diagnosis of Enteric Fever in Two Controlled Human Infection Models and an Endemic Area of Nepal. Front Microbiol. 2017 Oct 23;8:2031. doi: 10.3389/fmicb.2017.02031. eCollection 2017.
Results Reference
background
PubMed Identifier
27533046
Citation
Darton TC, Jones C, Blohmke CJ, Waddington CS, Zhou L, Peters A, Haworth K, Sie R, Green CA, Jeppesen CA, Moore M, Thompson BA, John T, Kingsley RA, Yu LM, Voysey M, Hindle Z, Lockhart S, Sztein MB, Dougan G, Angus B, Levine MM, Pollard AJ. Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a. PLoS Negl Trop Dis. 2016 Aug 17;10(8):e0004926. doi: 10.1371/journal.pntd.0004926. eCollection 2016 Aug.
Results Reference
result
Links:
URL
http://www.ovg.ox.ac.uk/
Description
Oxford Vaccine Group homepage
URL
https://pubmed.ncbi.nlm.nih.gov/29075261/
Description
Blohmke CJ, Hill J, Darton TC, Carvalho-Burger M, Eustace A, Jones C, Schreiber F, Goodier MR, Dougan G, Nakaya HI, Pollard AJ. Induction of Cell Cycle and NK Cell Responses by Live-Attenuated Oral Vaccines against Typhoid Fever.
URL
https://pubmed.ncbi.nlm.nih.gov/30252031/
Description
The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies
URL
https://pubmed.ncbi.nlm.nih.gov/26394303/
Description
Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans
URL
https://pubmed.ncbi.nlm.nih.gov/29387052/
Description
Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model
URL
https://pubmed.ncbi.nlm.nih.gov/29075261/
Description
Induction of Cell Cycle and NK Cell Responses by Live-Attenuated Oral Vaccines against Typhoid Fever
URL
https://pubmed.ncbi.nlm.nih.gov/35254093/
Description
Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers
URL
https://pubmed.ncbi.nlm.nih.gov/28970824/
Description
Identification of Novel Serodiagnostic Signatures of Typhoid Fever Using a Salmonella Proteome Array
URL
https://pubmed.ncbi.nlm.nih.gov/29109704/
Description
Assessment and Translation of the Antibody-in-Lymphocyte Supernatant (ALS) Assay to Improve the Diagnosis of Enteric Fever in Two Controlled Human Infection Models and an Endemic Area of Nepal

Learn more about this trial

Understanding Typhoid Disease After Vaccination

We'll reach out to this number within 24 hrs