PDF(Pubmed)
Abstract：
Invasive non-typhoidal Salmonella (iNTS) serovars are a major cause of community-acquired bloodstream infections in sub-Saharan Africa (SSA). In this setting, Salmonella enterica 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 Salmonella 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.
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 S. 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.
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.
NCT05870150.
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 S. 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.
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.
NCT05870150.
摘要：
背景：侵袭性非伤寒沙门氏菌（iNTS）血清型是撒哈拉以南非洲（SSA）社区获得性血流感染的主要原因。在此设置中，伤寒沙门氏菌占感染的三分之二，估计病死率为15％-20％。几种iNTS候选疫苗处于早期评估阶段，如果发现有效，将为减少iNTS疾病负担提供有价值的公共卫生工具。CHANTS研究旨在开发一种人类首次控制的鼠伤寒沙门氏菌感染模型，可以作为未来疫苗评估的平台，除了提供新的见解iNTS疾病的发病机制。
方法：这种双盲，安全性和剂量递增研究将对40-80名年龄在18-50岁的英国健康参与者进行随机分组,接受两种属于ST19(菌株4/74)或ST313(菌株D23580)谱系的鼠伤寒沙门氏菌菌株之一的口服攻击.4/74是一种全球毒株，通常与腹泻疾病相关，主要发生在高收入地区。而D23580是代表SSA中发现的侵袭性致病分离株的原型菌株。主要目标是确定60％-75％的参与者发展全身性沙门氏菌病的临床或微生物学特征所需的最小感染剂量（菌落形成单位）。次要终点是描述和比较临床，挑战后的微生物学和免疫学反应。剂量递增或递减将通过持续重新评估方法进行，并限制在预定的安全阈值内。探索性目标是描述iNTS毒力的机制，确定保护的推定免疫相关因素，并描述宿主-病原体相互作用以响应感染。
背景：已获得NHS健康研究管理局的道德批准（伦敦-富勒姆研究伦理委员会21/PR/0051；IRAS项目ID301659）。研究结果将在国际同行评审期刊上传播，并在国家/国际利益攸关方会议上发表。研究结果摘要将提供给资助者和参与者。
背景：NCT05870150。
方法：这种双盲，安全性和剂量递增研究将对40-80名年龄在18-50岁的英国健康参与者进行随机分组,接受两种属于ST19(菌株4/74)或ST313(菌株D23580)谱系的鼠伤寒沙门氏菌菌株之一的口服攻击.4/74是一种全球毒株，通常与腹泻疾病相关，主要发生在高收入地区。而D23580是代表SSA中发现的侵袭性致病分离株的原型菌株。主要目标是确定60％-75％的参与者发展全身性沙门氏菌病的临床或微生物学特征所需的最小感染剂量（菌落形成单位）。次要终点是描述和比较临床，挑战后的微生物学和免疫学反应。剂量递增或递减将通过持续重新评估方法进行，并限制在预定的安全阈值内。探索性目标是描述iNTS毒力的机制，确定保护的推定免疫相关因素，并描述宿主-病原体相互作用以响应感染。
背景：已获得NHS健康研究管理局的道德批准（伦敦-富勒姆研究伦理委员会21/PR/0051；IRAS项目ID301659）。研究结果将在国际同行评审期刊上传播，并在国家/国际利益攸关方会议上发表。研究结果摘要将提供给资助者和参与者。
背景：NCT05870150。
