Understanding How Salmonella Typhi Infects Humans (Bottlenecks)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03889067|
Recruitment Status : Active, not recruiting
First Posted : March 26, 2019
Last Update Posted : October 20, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Salmonella Typhi Infection||Biological: Salmonella Typhi challenge||Not Applicable|
The pathogenesis of bacteraemia for human restricted pathogens such as Streptococcus pneumoniae, Haemophilus influenzae type b and Salmonella enterica serovar Typhi (ST), have thus far only been investigated in imperfect animal models. The Salmonella Typhimurium mouse model is widely employed however there are key differences compared with S. Typhi. These bacteria are both genetically distinct and cause a different human disease phenotype . Data from a human model would be invaluable in furthering our understanding of bacteraemia in the human host. Animal studies with Salmonella species and other bacterial species show some evidence that there may be population bottlenecks in the development of blood stream infections.
Inoculation with many microorganisms is often sufficient to cause a blood stream infection in a susceptible host, typically inoculation with a single microorganism is not. There are two principle theories as to how bacteraemia arises. The first is independent action whereby the bacteraemia that results from bacterial inoculation is derived from a single founder organism ('the bottleneck hypothesis'). Each organism has a chance of being that founder organism. A greater number of organisms make bacteraemia more likely. The second theory is synergy where there is cooperation between bacteria, multiple bacteria traverse the barrier to infection and therefore the bacteraemia is composed of multiple variants.
The aim of this research project is to investigate the population bottleneck theory in the pathogenesis of bacteraemia in human infection model using a challenge combination of two isogenic strains of S. Typhi.
The primary objective of the study is to compare the number of participants who develop bacteraemia post challenge from each S. Typhi variant or a combination of the two strains. From animal models the investigators hypothesize that in an individual participant a single strain will be isolated more commonly than a combination of the two. The secondary objectives are to quantify the burden of bacteraemia of the two strains and to characterise the stool shedding in participants given a mixed inoculum.
Exploratory objectives include comparison of the number of participants who develop bacteraemia at various timepoints until 72 hours from each S. Typhi variant or a combination of the two strains. From animal models it is expected that any so-called 'primary bacteraemias' may involve a combination of the S. Typhi strains. The researchers also anticipate that stool cultures from study participants may culture a combination of the S. Typhi strains initially but that if a single isolate is cultured from the blood that this will be reflected in stool culture. The investigators will explore if quantitation of S. Typhi is possible in stool. They will also seek to evaluate the host immune response to challenge in terms of cytokine and blood transcriptional signatures.
This is the first time in which the bottleneck theory has been explored in a human model of a bloodstream infection. It will not only be significant for understanding the pathogenesis of S. Typhi but also for other bacterial pathogens. If this hypothesis is supported this implies that the barrier for vaccine prevention of bacterial infection may be lower than previously thought, perhaps only very few or even a single organism must be prevented from invasion to provide individual protection.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||11 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Ambulatory outpatient human experimental infection|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Exploring the Bottleneck Hypothesis of the Pathogenesis of Bacteraemia in an Ambulatory Outpatient Human Experimental Infection of Salmonella Typhi|
|Actual Study Start Date :||May 30, 2019|
|Estimated Primary Completion Date :||March 31, 2021|
|Estimated Study Completion Date :||September 30, 2021|
Experimental: Combination of Challenge Agents
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
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.
- Number of participants with a bacteraemia [ Time Frame: Two weeks after typhoid challenge ]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
- Number of isolates that are wild-type S.Typhi or Typhoid toxin knock-out strain [ Time Frame: Two months after typhoid challenge ]Number of isolates that are wild-type S.Typhi or Typhoid toxin knock-out strain obtained using quantitative blood cultures
- 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 [ Time Frame: Six weeks after typhoid challenge ]Number of participants with positive stool cultures 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 stool cultures
- Number of participants with a bacteraemia caused by wild-type S. Typhi or Typhoid toxin knock-out strain or a combination of both strains [ Time Frame: Two weeks after typhoid challenge ]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 (obtained at less than 72 hours post challenge)
- Proportion of stool culture isolates are wild-type S.Typhi or Typhoid toxin knock-out strain [ Time Frame: Six weeks after typhoid challenge ]To count what proportion of stool culture isolates are wild-type S.Typhi or Typhoid toxin knock-out strain obtained using quantitative stool cultures
- 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. [ Time Frame: 4 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03889067
|Centre for Clinical Vaccinology and Tropical Medicine (CCVTM)|
|Oxford, Oxfordshire, United Kingdom, OX3 7LE|
|Principal Investigator:||Andrew J Pollard, FRCPCH, PhD||University of Oxford|