Clinical Trial: Investigating Enteric Fever - Salmonella Typhi and Paratyphi Challenge Study

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Investigating the Mechanisms and Determinants of Systemic and Mucosal Immunity to Salmonella Typhi and Salmonella Paratyphi A in naïve and Previously Exposed Individuals - A Challenge and Rechall

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.

There are two main groups in this study. Firstly a group of 40 to 60 volunteers recruited from the community and not previously exposed to typhoidal Salmonella (part A); secondly a group of 20 to 60 volunteers from participants of previous challenge studies conducted by the Oxford Vaccine Group (part B).

Participants in part A and B will be randomly allocated one-to-one to have either S. Typhi or S. Paratyphi. The dose of bacteria has been determined by previous challenge studies to give an attack rate of 60 to 75% in individuals naive to typhoidal Salmonella. The bacteria is then ingested as a drink with a bicarbonate buffer ('the challenge').

In addition to these two groups, a preliminary study involving 3 to 10 participants to act as 'negative controls' will be performed. They will ingest the bicarbonate drink but not be given S. Typhi or S. Paratyphi. This group is not randomised with part A or B, and is unblinded i.e. the participant will be aware that they are not drinking typhoidal Salmonella. The participants will have all the same procedures and investigations as those in part A and B, including endoscopy with biopsies, daily visits during the two week intensive phase, and a course of antibiotics.

Prior to challenge, participants (from parts A, B and negative control group) will undergo endoscopy and tissue biopsies of the gut lining. This procedure will be repeated after the intensive phase and completion of a two week course of antibiotics.

After challenge, participants will be reviewed daily for at least 14 days by study investigators. Samples of blood, stool, saliva and urine will be collected. Participants diagnosed with enteric fever will be treated immediately with antibiotics and samples will be taken a
Sponsor: University of Oxford

Current Primary Outcome: Measure the attack rate after challenge with S. Typhi or S. Paratyphi A in naïve and previously challenged individuals. [ Time Frame: 12 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• To describe the human clinical response to S. Typhi or S. Paratyphi A in antigen-naïve and previously challenged individuals. [ Time Frame: 12 months ]
  The clinical response after challenge or re-challenge using participant symptom profiles, laboratory parameters (including inflammatory markers, blood count, liver function tests and microbiological culture results) will be used.
• 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. [ Time Frame: 12 months ]
  Microbiological culture (qualitative and quantitative) and polymerase chain reaction to detect and characterise S. Typhi or S. Paratyphi A in blood, stool and enteric fluid.
• To determine the gut luminal mucosal response to challenge with S. Typhi and S. Paratyphi. [ Time Frame: 12 months ]
  Mucosal inflammation as determined by (1) macroscopic appearance of mucosal inflammation as seen on endoscopy and wireless video capsule endoscopy (judged by experienced endoscopists), (2) inflammatory markers such as calprotectin and lactoferrin performed on stool and duodenal secretions.
• To describe the human immune response to challenge or re-challenge, including the innate, humoral, cell-mediated and mucosal responses. [ Time Frame: 12 months ]
  Assessed by immunological laboratory assays including quantitative and functional assays of the humoral (e.g. ELISA, enzyme-linked immunospot, serum bactericidal assay and opsonophagocytosis assay), mucosal (secretory immunoglobulin A measurement), and cell-mediated (multi-chromatic flow cytometry, mass cytometry, cytokine measurement) immune response.
• 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. [ Time Frame: 12 months ]

  Assessed by laboratory and high-throughput assays including:

  • measurement of baseline genetic susceptibility factors by whole genome sequencing
  • the transcriptional response to challenge and infection
  • detection of translated proteins by mass spectrometry (CyTOF).

Original Secondary Outcome: Same as current

Information By: University of Oxford

Dates:
Date Received: July 1, 2014
Date Started: December 2014
Date Completion: September 2019
Last Updated: May 4, 2017
Last Verified: May 2017