The Background, Role and Approach for Development of a Controlled Human Infection Model for Nontyphoidal Salmonella

Abstract

Nontyphoidal Salmonella (NTS) is responsible for a major global burden of disease and economic loss, particularly in low-and middle-income countries. It is designated a priority pathogen by the WHO for vaccine development and, with new impetus from vaccine developers, the establishment of an NTS controlled human infection model (CHIM) is timely and valuable. The broadly dichotomous clinical presentations of diarrhoea or invasive disease, commonly bacteraemia, present significant challenges to the development of an NTS CHIM. Nevertheless, if successful, such a CHIM will be invaluable for understanding the pathogenesis of NTS disease, identifying correlates of protection and advancing candidate vaccines towards licensure. This article describes the background case for a CHIM for NTS, the role of such a CHIM and outlines a potential approach to its development. KeywordsNontyphoidal/Salmonella/CHIM/human challenge/vaccine/correlates of protection/pathogenesis MacLennanCA v2.2 NTS CHIM 2021110

The Challenge Non-Typhoidal Salmonella (CHANTS) Consortium: Development of a non-typhoidal Salmonella controlled human infection model: Report from a consultation group workshop, 05 July 2022, London, UK

“…Many of these models have provided valuable pre-clinical insights into host-pathogen interactions but do not always replicate the manifestations of disease in a context relevant for vaccine development. Historically, human challenge with wild-type or attenuated NTS serovars has been performed in a small number of volunteers, but a large-scale programme of activities for vaccine assessment has not previously been established 18 .…”

“…These uncertainties have been discussed at several expert meetings in the preceding years and have been discussed elsewhere 18 , 19 . Acknowledging the gaps which remain in this field, it was concluded that to address these questions, a CHIM could be established to characterise the response to wild type NTS challenge in order to understand if – and how – a human challenge model of NTS disease could be used for future vaccine assessment.…”

“…Unlike other enteric pathogens, there is relatively limited experience of controlled human infection studies of non-typhoidal Salmonella serovars 15 – 17 . The use-case for an NTS CHIM in vaccine assessment is controversial 18 , 19 . Recently, the Wellcome Trust has funded the establishment of the Challenge Non-Typhoidal Salmonella (CHANTS) consortium, to develop a first-in-human model of Salmonella Typhimurium infection using contemporary strains.…”