Abstract
<jats:p> Background: Invasive non-typhoidal <jats:italic>Salmonella</jats:italic> (iNTS) disease causes an estimated 605,000 cases and 76,000 deaths each year, concentrated in sub-Saharan Africa, where the African <jats:italic>Salmonella</jats:italic> Typhimurium sequence type 313 (ST313) lineage predominates. Vaccine development is hampered by an absence of efficacy data and undefined correlates of protection. Methods: We conducted a phase 1, randomised, double-blind, dose-escalation controlled human infection model (CHIM) in healthy UK-resident adults, who were randomly assigned 1:1 to oral challenge with <jats:italic>S</jats:italic> . Typhimurium 4/74 (ST19, associated with gastrointestinal disease) or D23580 (ST313, associated with invasive disease). Dose-escalation was guided by a Bayesian continual reassessment method (CRM). The primary endpoint was <jats:italic>Salmonella</jats:italic> diagnosis, defined as sustained fever ≥38°C on ≥2 occasions ≥12 hours apart and/or bacteraemia. Trial registration ClinicalTrials.gov ( <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT05870150">NCT05870150</jats:ext-link> ). Findings: Between August 2023 and December 2024, 50 participants were enrolled (25 per strain). 10 <jats:sup>5</jats:sup> CFU was the maximum feasible dose, with CRM-estimated attack rates of 57.9% (95% credible interval 37.3 - 73.8) for D23580 and 47.4% (26.7 - 65.7) for 4/74. There were no serious adverse events. We found no clinical, microbiological, or immunological difference between the two pathovariants. Higher baseline serum anti-O-antigen IgG was associated with reduced disease (adjusted OR 0.42, 95% CI 0.17 - 0.90) and higher baseline faecal anti-lipopolysaccharide IgA with reduced colonisation (OR 0.12, 95% CI 0.01 - 0.59). Interpretation: This <jats:italic>S</jats:italic> . Typhimurium CHIM is safe, reproducible, and provides a platform to generate early efficacy signals and candidate correlates of susceptibility, thereby de-risking future iNTS vaccine trials. The absence of a phenotypic difference between the invasive and gastrointestinal pathovariants in immunocompetent adults suggests that host factors, rather than pathogen adaptation alone, shape the invasive phenotype seen in endemic settings. Funding: Wellcome Trust. </jats:p>