Investigating Enteric Fever - Salmonella Typhi and Paratyphi Challenge Study
Condition: Typhoid Fever; Paratyphoid Fever
MeSH terms: Typhoid Fever; Paratyphoid Fever; Fever; Hyperthermia
Study type: Interventional

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.
    

Detailed description: 
      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 as per the protocol. The participants who do not meet criteria for enteric fever will
      be treated with antibiotics on Day 14.

      Enteric fever is diagnosed if any of the following apply:

        1. A positive blood culture for S. Typhi or Paratyphi from 72 hours post-challenge,

        2. a positive blood culture for S. Typhi or Paratyphi within 72 hours post-challenge, with
           one or more signs/symptoms of enteric fever,

        3. persistent positive blood cultures (two or more blood cultures taken at least 4 hours
           apart) for S. Typhi or Paratyphi within 72 hours postchallenge, or

        4. oral temperature ≥ to 38°C persisting for 12 hours.

      A proportion of participants from Part A and B will be offered the optional procedures of
      enteric string tests (also called Enterotest) and/or Wireless Video Capsule Endoscopies
      (WCE). Participants consenting to these procedures will be selected sequentially until the
      quota has been filled for each group.
    

Intervention name(s): Salmonella Typhi; Salmonella Paratyphi
Intervention type(s): Biological; Biological
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Challenge; Re-challenge; Controlled Infection; Enteric fever