Investigating Enteric Fever - Salmonella Typhi and Paratyphi Challenge Study

NCT02192008 | Completed DMC

• 1 other identifier: OVG 2014/01
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 1

Brief Summary

Enteric fever, an infection characterised by diarrhoea and rash, is most often caused by a bacteria called Salmonella enterica. After ingesting contaminated food or drink, the Salmonellae travel first to the gut, then the bloodstream, from where they can infect other parts of the body. Antibiotics are used to kill the bacteria, but with increasing rates of antibiotic resistance, this treatment is becoming less effective. Two Salmonella variants, Typhi and Paratyphi, cause over 30 million cases of enteric fever and more than 200,000 deaths per year, mostly in developing countries. While improved hygiene and sanitation should eventually eliminate enteric fever, reduction of the disease burden in the medium term is achievable through effective vaccination. Vaccines likely to be available for mass vaccination are effective only against those Salmonella strains that bear the Vi polysaccharide capsule protein. Strains that do not have these capsule proteins, or have no capsule, will not be affected by vaccination and could 'fill' the space vacated by the capsulated strains. Indeed, enteric fever caused by S. Paratyphi A which does not carry the Vi protein, has risen during the past decade and accounts for more than half of all cases in some areas. Thus it is important that effective vaccines are available to protect against infection by both capsulated and noncapsulated Salmonella enterica. To develop such vaccines, we need a complete understanding of the human immune response to both types, including the contribution of immunity in the gut and the bloodstream, immune response to bacterial surface proteins, and the role of antibodies. How much cross-protection there is between the types of typhoidal Salmonellae after natural infection or vaccination is not known, but this is critical to vaccine development. This project aims to fill in the knowledge gaps highlighted, by fully characterising the infection process and immune response in enteric fever.

Conditions

Typhoid Fever; Paratyphoid Fever

Keywords

Challenge; Re-challenge; Controlled Infection; Enteric fever

Outcome Measures

Primary Outcomes (1)

• Measure the attack rate after challenge with S. Typhi or S. Paratyphi A in naïve and previously challenged individuals.

  Based on clinical and/or microbiological proven enteric fever infection.

  12 months

Secondary Outcomes (5)

• To describe the human clinical response to S. Typhi or S. Paratyphi A in antigen-naïve and previously challenged individuals.

  12 months

• To describe the characteristics of bacterial dynamics after challenge in naïve and previously exposed individuals, including onset and duration of bacteraemia, bacterial burden at diagnosis, bacterial burden in enteric fluid, and stool shedding.

  12 months

• To determine the gut luminal mucosal response to challenge with S. Typhi and S. Paratyphi.

  12 months

• To describe the human immune response to challenge or re-challenge, including the innate, humoral, cell-mediated and mucosal responses.

  12 months

• Determine host genetic features influencing: • clinical manifestations of challenge with typhi/paratyphi • alteration of those responses through epigenetic changes • and control of gene and protein expression.

  12 months

Other Outcomes (3)

• Exploratory immunology to investigate the innate, humoral, cell-mediated and mucosal responses to challenge with S. Typhi or S. Paratyphi A in naïve and previously challenged individuals.

  5 years

• To investigate how the human microbiome influences and interacts with a challenge of S. Typhi or S. Paratyphi A

  5 years

• Investigate new molecular techniques for detection of S. Typhi and/or S. Paratyphi in clinical samples.

  5 years

Study Arms (2)

Part A

ACTIVE COMPARATOR

Cohort naive to typhoidal Salmonella challenged with either S. Typhi or S. Paratyphi

Biological: Salmonella Typhi; Biological: Salmonella Paratyphi

Part B

ACTIVE COMPARATOR

Cohort previously challenged with S. Typhi or Paratyphi re-challenged with either S. Typhi or S. Paratyphi.

Biological: Salmonella Typhi; Biological: Salmonella Paratyphi

Interventions

Salmonella Typhi BIOLOGICAL

Part A; Part B

Salmonella Paratyphi BIOLOGICAL

Part A; Part B

Eligibility Criteria

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

You may qualify if:

• In good health as determined by medical history, physical examination and clinical judgment of the investigators.
• Agree (in the Investigator'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 Public Health England to be informed of their participation in the study .
• Agree to give his or her close household contacts written information informing them of the participants' involvement in the study and offering them voluntary screening for S. Typhi or S. Paratyphi 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.
• Have internet access to allow completion of the e-diary and real-time safety monitoring.
• Agree to avoid antipyretic/anti-inflammatory treatment until advised by a study doctor or until at least 14 days after challenge.
• Willing to undergo endoscopy and biopsy.

You may not qualify if:

• History of significant organ/system disease that could interfere with study conduct or completion.
• Have any known or suspected impairment of immune function, alteration of immune function, or prior immune exposure that may alter immune function.
• Moderate or severe depression or anxiety as classified by the Hospital Anxiety and Depression Score at screening or challenge that is deemed clinically significant by the study investigators.
• Weight 50kg or less.
• Presence of implants or prosthesis.
• Have previously received any typhoid vaccine
• Any contraindication to elective upper GI endoscopy.
• More than one non-study related upper GI endoscopy within the last year.
• Anyone taking long-term medication that may affect symptom reporting or interpretation of the study results.
• Contra-indication to taking ciprofloxacin, azithromycin, trimethoprim/ sulfamethoxazole and/or beta lactam antibiotics.
• Female participants who are pregnant or lactating.
• Female participants who are unwilling to ensure that they or their partner use effective contraception one month prior to challenge and continue to do so until two negative stool samples, a minimum of three weeks after completion of antibiotic treatment, have been obtained.
• Full-time, part-time or voluntary occupations involving clinical or social work with direct contact with young children (defined as those attending pre-school groups or nursery or aged under 2 years); clinical or social work with direct contact with highly susceptible patients or persons in whom typhoid or paratyphoid infection would have particularly serious consequences e.g. the elderly or infirm.
• Full time, part time or voluntary occupations involving commercial food handling.
• Close household contact with young children (defined as those attending pre-school groups, nursery or those aged less than 2 years), individual(s) who is (are) immunocompromised, scheduled elective surgery or other procedures requiring general anaesthesia during the study period.

Sponsors & Collaborators

• University of Oxford: lead
• University of Liverpool: collaborator
• Brigham and Women's Hospital: collaborator

Study Sites (1)

Oxford Vaccine Group

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

Related Publications (2)

• Gibani MM, Jin C, Shrestha S, Moore M, Norman L, Voysey M, Jones E, Blackwell L, Thomaides-Brears H, Hill J, Blohmke CJ, Dobinson HC, Baker P, Jones C, Campbell D, Mujadidi YF, Plested E, Preciado-Llanes L, Napolitani G, Simmons A, Gordon MA, Angus B, Darton TC, Cerundulo V, Pollard AJ. Homologous and heterologous re-challenge with Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled human infection model. PLoS Negl Trop Dis. 2020 Oct 20;14(10):e0008783. doi: 10.1371/journal.pntd.0008783. eCollection 2020 Oct.

  PMID: 33079959 BACKGROUND

• Jin C, Gibani MM, Pennington SH, Liu X, Ardrey A, Aljayyoussi G, Moore M, Angus B, Parry CM, Biagini GA, Feasey NA, Pollard AJ. Treatment responses to Azithromycin and Ciprofloxacin in uncomplicated Salmonella Typhi infection: A comparison of Clinical and Microbiological Data from a Controlled Human Infection Model. PLoS Negl Trop Dis. 2019 Dec 26;13(12):e0007955. doi: 10.1371/journal.pntd.0007955. eCollection 2019 Dec.

  PMID: 31877141 DERIVED

Related Links

• Homologous and heterologous re-challenge with Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled human infection model
• Related Info
• Related Info

MeSH Terms

Conditions

Typhoid Fever; Paratyphoid Fever

Condition Hierarchy (Ancestors)

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

Study Officials

• Andrew Pollard, FRCPCH, PhD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: July 1, 2014
• First Posted: July 16, 2014
• Study Start: December 1, 2014
• Primary Completion: September 22, 2018
• Study Completion: May 26, 2022
• Last Updated: June 2, 2022

Record last verified: 2021-01

Locations

GB (1)