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

Abstract

Invasive non-typhoidal Salmonella disease (iNTS) is a major cause of morbidity and mortality globally, particularly as a cause of bloodstream infection in children and immunocompromised adults in sub-Saharan Africa. Vaccines to prevent non-typhoidal Salmonella (NTS) would represent a valuable public health tool in this setting to avert cases and prevent expansion of antimicrobial resistance. Several NTS and combination typhoidal-NTS vaccine candidates are in early-stage development, although the pathway to licensure is unclear due to challenges in conducting large phase III field trials. Controlled human infection models (CHIM) present an opportunity to accelerate vaccine development for a range of enteric pathogens. Several recent typhoidal Salmonella CHIMs have been conducted safely and have played pivotal roles in progressing vaccine candidates to pre-qualification and licensure. The Challenge Non-Typhoidal Salmonella (CHANTS) consortium has been formed with funding from the Wellcome Trust, to deliver the first NTS CHIM, which can act as a platform for future vaccine evaluation. This paper reports the conclusions of a consultation group workshop convened with key stakeholders. The aims of this meeting were to: (1) define the rationale for an NTS CHIM (2) map the NTS vaccine pipeline (3) refine study design and (4) establish potential future use cases.

Protocol for the challenge non-typhoidalSalmonella(CHANTS) study: a first-in-human, in-patient, double-blind, randomised, safety and dose-escalation controlled human infection model in the UK

“…The rationale for strains selected for use in this model, and their relative merits, have been discussed in detail elsewhere. 21 We hypothesise that ST313 (D23580) will be associated with an invasive phenotype compared with the enterocolitis anticipated as a result of challenge with ST19 (4/74).…”

“…Both strains are susceptible to ciprofloxacin, azithromycin and third-generation cephalosporins, ensuring a range of treatment options are available for challenged participants. The rationale for strains selected for use in this model, and their relative merits, have been discussed in detail elsewhere 21. We hypothesise that ST313 (D23580) will be associated with an invasive phenotype compared with the enterocolitis anticipated as a result of challenge with ST19 (4/74).…”

“…We have elected to offer rescue treatment in specific circumstances. The rationale for this decision is discussed elsewhere 21. Antibiotic therapy will be initiated in all participants who fulfil criteria for Salmonella diagnosis through reaching either or both of the defined primary endpoints of persistent fever or BSI.…”

“…Potential risks have been given extensive consideration, with risk mitigation strategies devised to minimise possible impact on participants. The potential complications of participation—and risk mitigation strategies—have been discussed elsewhere 21. In addition to participant safety, careful consideration has been given to ensure safety of study investigators and close contacts.…”

“…However, in view of the heterogeneous clinical phenotypes associated with NTS infection, ranging from asymptomatic colonisation to septic shock, this endpoint is felt to represent the optimal trade-off between clinical manifestations of disease and patient safety within the context of a CHIM. The relative merits of endpoint selection and their rationale have been discussed previously 21…”