Understanding How Salmonella Typhi Infects Humans (Bottlenecks)

NCT03889067 | Completed DMC

• 1 other identifier: OVG/2018/06
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

Typhoid fever is an infection caused by the bacteria Salmonella Typhi (S. Typhi). S. Typhi causes disease principally in developing countries where communities do not have access to safe water or adequate sanitation. It is thought to cause illness in approximately 22 million people every year and up to 200,000 deaths, mostly in children. The bacteria are spread when faeces from infected individuals contaminate food and water sources. Symptoms of infection include headache, fever and general aches and pains. If not treated properly typhoid infection can lead to severe complications and even death. In this study the investigators aim to understand more about the S. Typhi bacteria and how S. Typhi causes a bloodstream infection after it has been ingested and passed into the gut. In spite of the extensive morbidity and mortality associated with bacterial blood stream infections (BSI), comparatively little is known about the pathogenesis. At a time of increasing antimicrobial resistance and a lack of new antimicrobial agents, understanding the pathogenesis of BSI is essential for efforts directed at prevention both of Salmonella Typhi and other bacterial species, particularly those that are restricted to humans.

Conditions

Salmonella Typhi Infection

Keywords

Enteric fever; Typhoid; Salmonella Typhi; Typhoid fever; Salmonella infections; Gram-negative bacterial infections; Human model of infection

Outcome Measures

Primary Outcomes (1)

• Number of participants with a bacteraemia

  Number of participants with a bacteraemia caused by wild-type S. Typhi or Typhoid toxin knock-out strain or a combination of both strains as assessed by identification of strains isolated from blood cultures

  Two weeks after typhoid challenge

Secondary Outcomes (2)

• Number of isolates that are wild-type S.Typhi or Typhoid toxin knock-out strain

  Two months after typhoid challenge

• umber of participants with positive stool cultures caused by wild-type S. Typhi or Typhoid toxin knock-out strain or a combination of both strains

  Six weeks after typhoid challenge

Other Outcomes (3)

• Number of participants with a bacteraemia caused by wild-type S. Typhi or Typhoid toxin knock-out strain or a combination of both strains

  Two weeks after typhoid challenge

• Proportion of stool culture isolates are wild-type S.Typhi or Typhoid toxin knock-out strain

  Six weeks after typhoid challenge

• Number of responses obtained from each recruitment method used and number of responses which translated into participants. Number of participants excluded and reasons for exclusion.

  4 weeks after typhoid challenge

Study Arms (1)

Combination of Challenge Agents

EXPERIMENTAL

Wild-Type Quailes Strain Salmonella Typhi: Quailes Typhoid toxin knock out strain in a 1:1 ratio at a dose of 1-5 x 10\^4CFU All participants will receive the same intervention in a given group for challenge (dose reduction may occur for later participants depending on the results from the first six participants)

Biological: Salmonella Typhi challenge

Interventions

Salmonella Typhi challenge BIOLOGICAL

The challenge agents will be delivered in 30 ml of sodium bicarbonate solution, preceded by 120 ml of solution of sodium bicarbonate to neutralise gastric acid.

Combination of Challenge Agents

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 GP (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 medical history and vaccination records.
• 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 are 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 on a daily basis 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 (The Over volunteering Prevention System) registration and 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 current 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

Study Sites (1)

Centre for Clinical Vaccinology and Tropical Medicine (CCVTM)

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

MeSH Terms

Conditions

Typhoid Fever; Salmonella Infections; Gram-Negative Bacterial Infections

Condition Hierarchy (Ancestors)

Enterobacteriaceae Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Andrew J Pollard, FRCPCH, PhD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Ambulatory outpatient human experimental infection

Study Record Dates

• First Submitted: March 5, 2019
• First Posted: March 26, 2019
• Study Start: May 30, 2019
• Primary Completion: November 11, 2021
• Study Completion: November 11, 2021
• Last Updated: February 9, 2022

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)