Investigating Typhoid Fever Pathogenesis

NCT03067961 | Unknown DMC

• 1 other identifier: OVG 2016/03
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Typhoid fever results from infection with a bacterium called Salmonella Typhi and is a major cause of illness worldwide. It is estimated to infect 20-25 million people every year and can affect people of all ages, but is particularly common in young children. The disease is spread through contaminated food and water, and efforts to improve water quality, sanitation and hygiene will likely go a long way to reducing the global burden of disease. Unfortunately, improving access to clean water and sanitation improvements is very costly and difficult to implement on a large scale. Vaccination against typhoid fever is likely to be a cost-effective way of reducing the global disease burden. There are two vaccines currently available against typhoid fever. Whilst these vaccines provide some protection against disease (in the region of 50-70%) these vaccines are less effective in young children, who are the population group at highest risk of disease. In order to develop a new generation of typhoid vaccines it is important to have a more complete understanding of how the bacterium causes disease. In this study, the investigators are aiming to understand more about the Salmonella Typhi bacteria and how it causes disease. In particular, the investigators aim to study the importance of a toxin produced by the typhoid bacteria, called the typhoid toxin. The typhoid toxin has only recently been discovered. It is made only by the typhoid bacteria and closely related bacteria, such as paratyphoid. From studies done in the laboratory, there is evidence that the typhoid toxin is important in causing typhoid disease. It is thought that the typhoid toxin might be important in causing symptoms of typhoid disease, however the exact role of the typhoid toxin during infection in humans hasn't been studied before. Studying this might impact on the design new vaccines against typhoid. In this study, the investigators will be undertaking a 'challenge' with two strains of the typhoid bacteria (Salmonella Typhi). This involves exposing participants to live Salmonella Typhi under defined circumstances, by asking them to swallow a solution that contains the bacteria. After the challenge the investigators closely monitor participants for a period of at least two weeks and the investigators will then treat participants with antibiotics as soon as they are diagnosed with typhoid disease. The investigators are interested in comparing the response to challenge between two strains of the typhoid bacteria that differ in the production of the typhoid toxin. This process has been undertaken by participants in previous Oxford Vaccine Group studies since 2011.

Conditions

Salmonella Typhi Infection

Keywords

Enteric fever; Typhoid; Salmonella Typhi; Challenge study; Human model of infection; Typhoid toxin

Outcome Measures

Primary Outcomes (1)

• Clinical or microbiologically proven typhoid infection

  The proportion of participants developing clinical or microbiologically proven typhoid infection following oral challenge with 1-5x104 CFU wild type S. Typhi Quailes strain (WT) delivered in a sodium bicarbonate solution, in comparison to challenge with 1-5x104 CFU of a typhoid toxin-deficient isogenic mutant of S. Typhi Quailes strain SB6000 (TN). Typhoid fever diagnosis defined as defined as either: i) A positive blood culture for S. Typhi from 72 hours post-challenge or; ii) A positive blood culture for S. Typhi within 72 hours post-challenge, with one or more signs/symptoms of typhoid infection (such as recorded temperature ≥38.0oC) or; (iii) Persistent positive blood cultures (two or more blood cultures taken at least 4 hours apart) for S. Typhi within 72 hours post-challenge or; (iv) Oral temperature ≥38.0oC persisting for 12 hours.

  Up to 14 days after challenge dose administered

Secondary Outcomes (13)

• Clinical features following challenge with either wild-type S. Typhi Quailes strain (WT) or typhoid toxin-deficient isogenic mutant S. Typhi Quailes strain SB6000 (TN).

  Up to one year after challenge

• Clinical features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain

  Up to one year after challenge

• Clinical features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain

  Up to one year after challenge

• Clinical features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain

  Up to one year after challenge

• Clinical features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain

  Up to one year after challenge

Study Arms (2)

Wild type S. Typhi Quailes strain

EXPERIMENTAL

Administered by the oral route with sodium bicarbonate at a dose of 1-5x10 4 CFU.

Other: Salmonella Typhi (S. Typhi)

Quailes typhoid toxin knock-out

EXPERIMENTAL

Administered by the oral route with sodium bicarbonate at a dose of 1-5x10 4 CFU.

Other: Salmonella Typhi (S. Typhi)

Interventions

Salmonella Typhi (S. Typhi) OTHER

Investigating the role of typhoid toxin in the pathogenesis of enteric fever

Quailes typhoid toxin knock-out; Wild type S. Typhi Quailes strain

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participants must satisfy all of the following criteria to be considered eligible for the study:
• Agree to give informed consent for participation in the study.
• Aged between 18 and 60 years inclusive at time of challenge.
• In good health as determined by medical history, physical examination and clinical judgment of the study team.
• Agree (in the study team's opinion) to comply with all study requirements, including capacity to adhere to good personal hygiene and infection control precautions.
• Agree to allow his or her General Practitioner (and/or Consultant if appropriate), to be notified of participation in the study.
• Agree to allow study staff to contact his or her GP to access the participant's vaccination records and summary of medical history.
• Agree to allow Public Health England to be informed of their participation in the study.
• Agree to give his or her close contacts written information informing them of the participant's involvement in the study and offer them voluntary screening for S. Typhi carriage.
• Agree to have 24-hour contact with study staff during the four weeks post challenge and to be able to ensure that they are contactable by mobile phone for the duration of the challenge period until antibiotic completion.
• Agree to allow the study team to hold the name and 24-hour contact number of a close friend, relative or housemate who will be kept informed of the study participant's whereabouts for the duration of the challenge period (from the time of challenge until completion of antibiotic course). This person will be contacted if study staff are unable to contact the participant.
• Have internet access to allow completion of the e-diary and real-time safety monitoring.
• Agree to avoid antipyretic/anti-inflammatory treatment from the time of challenge (Day 0) until advised by a study doctor or until 14 days after challenge.
• Agree to refrain from donating blood for the duration of the study.
• Agree to provide their National Insurance/Passport number for the purposes of TOPS registration and bank account details for payment of reimbursement expenses.

You may not qualify if:

• The participant will not be enrolled if any of the following apply:
• History of significant organ/system disease that could interfere with trial conduct or completion. Including, for example, but not restricted to:
• Cardiovascular disease
• Respiratory disease
• Haematological disease
• Endocrine disorders
• Renal or bladder disease, including history of renal calculi
• Biliary tract disease, including biliary colic, asymptomatic gallstones or previous cholecystectomy
• Gastro-intestinal disease including requirement for antacids, H2-receptor antagonists, proton pump inhibitors or laxatives
• Neurological disease
• Metabolic disease
• Autoimmune disease
• Psychiatric illness requiring hospitalisation or known or suspected drug and/or alcohol misuse (alcohol misuse defined as an intake exceeding 42 units per week)
• Infectious disease
• Have any known or suspected impairment of immune function, alteration of immune function, or prior immune exposure that may alter immune function to typhoid resulting from, for example:

Sponsors & Collaborators

• University of Oxford: lead
• Bill and Melinda Gates Foundation: collaborator
• Yale University: collaborator

Study Sites (1)

Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

Related Links

• Related Info

MeSH Terms

Conditions

Typhoid Fever

Condition Hierarchy (Ancestors)

Salmonella Infections; Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Andrew J Pollard

  Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Oxford, Oxfordshire, United Kingdom, OX3 7LE

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2016
• First Posted: March 1, 2017
• Study Start: February 27, 2017
• Primary Completion: August 15, 2018
• Study Completion: September 30, 2022
• Last Updated: December 10, 2021

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)