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Understanding Typhoid Disease After Vaccination

This study is ongoing, but not recruiting participants.
Wellcome Trust
Imperial College London
University of Maryland
Information provided by (Responsible Party):
University of Oxford Identifier:
First received: July 28, 2011
Last updated: October 13, 2016
Last verified: October 2016

July 28, 2011
October 13, 2016
December 2011
December 2015   (final data collection date for primary outcome measure)
Diagnosis of typhoid fever [ Time Frame: 2 weeks after typhoid challenge ] [ Designated as safety issue: No ]

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).

Same as current
Complete list of historical versions of study NCT01405521 on Archive Site
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Understanding Typhoid Disease After Vaccination
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.
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.

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.

Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
  • Typhoid Fever
  • Enteric Fever
  • Typhoid
  • Biological: Vaccine placebo (excipients only)
    single oral dose,
  • Biological: Ty21a
    3 oral doses, alternate days
    Other Name: Vivotif
  • Biological: M10ZH09 vaccine
    single oral dose
    Other Name: Typhella
  • Experimental: M01ZH09 vaccine
    Intervention: Biological: M10ZH09 vaccine
  • Placebo Comparator: Vaccine placebo
    Intervention: Biological: Vaccine placebo (excipients only)
  • Ty21a vaccine
    Positive control
    Intervention: Biological: Ty21a
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.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Active, not recruiting
December 2016
December 2015   (final data collection date for primary outcome measure)

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.
18 Years to 60 Years   (Adult)
Contact information is only displayed when the study is recruiting subjects
United Kingdom
OVG 2011/02, 2011-000381-35
Not Provided
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University of Oxford
University of Oxford
  • Wellcome Trust
  • Imperial College London
  • University of Maryland
Principal Investigator: Andrew J Pollard Oxford Vaccine Group, Department of Paediatrics, University of Oxford
University of Oxford
October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP