Protocol for the challenge non-typhoidal <i>Salmonella</i> (CHANTS) study: a first-in-human, in-patient, double-blind, randomised, safety and dose-escalation controlled human infection model in the UK.


Smith, Christopher ORCID: 0000-0001-7369-2034, Smith, Emma, Rydlova, Anna, Varro, Robert, Hinton, Jay CD ORCID: 0000-0003-2671-6026, Gordon, Melita A ORCID: 0000-0002-0629-0884, Choy, Robert KM, Liu, Xinxue ORCID: 0000-0003-1107-0365, Pollard, Andrew J ORCID: 0000-0001-7361-719X, Chiu, Christopher et al (show 2 more authors) (2024) Protocol for the challenge non-typhoidal <i>Salmonella</i> (CHANTS) study: a first-in-human, in-patient, double-blind, randomised, safety and dose-escalation controlled human infection model in the UK. BMJ open, 14 (1). e076477-.

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Abstract

<h4>Introduction</h4>Invasive non-typhoidal <i>Salmonella</i> (iNTS) serovars are a major cause of community-acquired bloodstream infections in sub-Saharan Africa (SSA). In this setting, <i>Salmonella enterica</i> serovar Typhimurium accounts for two-thirds of infections and is associated with an estimated case fatality rate of 15%-20%. Several iNTS vaccine candidates are in early-stage assessment which-if found effective-would provide a valuable public health tool to reduce iNTS disease burden. The CHANTS study aims to develop a first-in-human <i>Salmonella</i> Typhimurium controlled human infection model, which can act as a platform for future vaccine evaluation, in addition to providing novel insights into iNTS disease pathogenesis.<h4>Methods and analysis</h4>This double-blind, safety and dose-escalation study will randomise 40-80 healthy UK participants aged 18-50 to receive oral challenge with one of two strains of <i>S</i>. Typhimurium belonging to the ST19 (strain 4/74) or ST313 (strain D23580) lineages. 4/74 is a global strain often associated with diarrhoeal illness predominantly in high-income settings, while D23580 is an archetypal strain representing invasive disease-causing isolates found in SSA. The primary objective is to determine the minimum infectious dose (colony-forming unit) required for 60%-75% of participants to develop clinical or microbiological features of systemic salmonellosis. Secondary endpoints are to describe and compare the clinical, microbiological and immunological responses following challenge. Dose escalation or de-escalation will be undertaken by continual-reassessment methodology and limited within prespecified safety thresholds. Exploratory objectives are to describe mechanisms of iNTS virulence, identify putative immune correlates of protection and describe host-pathogen interactions in response to infection.<h4>Ethics and dissemination</h4>Ethical approval has been obtained from the NHS Health Research Authority (London-Fulham Research Ethics Committee 21/PR/0051; IRAS Project ID 301659). The study findings will be disseminated in international peer-reviewed journals and presented at national/international stakeholder meetings. Study outcome summaries will be provided to both funders and participants.<h4>Trial registration number</h4>NCT05870150.

Item Type: Article
Uncontrolled Keywords: Humans, Salmonella, Typhoid Fever, Vaccines, London, Randomized Controlled Trials as Topic, Singing
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User: Symplectic Admin
Date Deposited: 16 Jan 2024 11:01
Last Modified: 26 Feb 2024 06:30
DOI: 10.1136/bmjopen-2023-076477
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3177863
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