BACKGROUND: Invasive non-typhoid Salmonella (iNTS) is a leading cause of morbidity and mortality in sub-Saharan Africa. We assess the safety and immunogenicity of an outer membrane vesicle vaccine (iNTS-GMMA) derived from the two most common serovars, S. Enteritidis (SEn) and S. Typhimurium (STm). METHODS: This single centre, randomised within cohort, placebo-controlled dose escalation single-blind with blinded assessment trial included healthy people aged 18-55 according protocol eligibility criteria. A sentinel cohort (Group 1) was randomised 1:1 to a lower dose (10.6 μg total O-antigen [OAg]) or placebo, a subsequent cohort was randomised 1:1 to the full dose (40 μg total OAg) or placebo (Group 2), and the last cohort was randomised 2:1 (Group 3) to the full dose (40 μg total OAg) or placebo at CCVTM, University of Oxford. Participants received three intra-muscular administrations at 0, 2 and 6 months. EudraCT Number 2020-000510-14. FINDINGS: Between May and November 2022, 7 participants were assigned to Group 1, 6 to Group 2 and 18 to Group 3. 26/31 completed follow-up at 12 months. No SAEs or SUSARs were reported. The most common adverse events (AE) were injection site reactions. All participants (19/19, 100%) in the iNTS-GMMA groups reported at least one solicited AEs, which were mostly mild to moderate in severity. 28 days following vaccination, unsolicited AEs at least possibly related to iNTS-GMMA were predominantly mild (6, 50%) and (4, 33.3%) moderate. An increase from baseline in serovar-specific OAg IgG levels peaked at day 28 following full dose (SEn: GMC 865.4 [95% CI 404.9, 1849.6]; STm: 833.2 [401.8, 1727.9]) compared with placebo (SEn: 73.7 [22.4, 242.3]; STm: 41.1 [17.6, 95.5]). Serum bactericidal antibody (SBA) peaked at day 28 following first vaccination (SEn: 38,722.7 [14,209, 105,528.1]; STm: 29,989 [18,528.6, 48,537.9]) compared with placebo (SEn: 9976 [4261.1, 23,355.5]; STm: 6694.3 [2742, 16,343.6]). INTERPRETATION: The iNTS-GMMA vaccine was immunogenic and did not show safety concerns precluding further development, supporting progression to further phase I and II clinical trials. FUNDING: EU Framework Programme for Research and Innovation grant, Horizon 2020 (grant agreement number 815439).