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Randomized Controlled Trial
. 2025 Sep:119:105903.
doi: 10.1016/j.ebiom.2025.105903. Epub 2025 Sep 3.

Safety and immunogenicity of the invasive non-typhoidal Salmonella (iNTS)-GMMA vaccine: a first-in-human, randomised, dose escalation trial

Brama Hanumunthadu  1 , Tesfaye Demissie  2 , Melanie Greenland  2 , Peter Skidmore  2 , Kiarash Tanha  2 , Tim Crocker-Buque  2 , Nelly Owino  2 , Antonella Silvia Sciré  3 , Chiara Crispino  3 , Daniele De Simone  3 , Marta Benincasa  3 , Maria Grazia Aruta  3 , Omar Rossi  3 , Anna Maria Colucci  3 , Francesco Berlanda Scorza  3 , Ashwani Kumar Arora  3 , Xinxue Liu  2 , Elizabeth A Clutterbuck  2 , Leila Godfrey  2 , Rocio Canals  3 , Maheshi N Ramasamy  4 ; Vacc-iNTS Consortium
Collaborators, Affiliations
Randomized Controlled Trial

Safety and immunogenicity of the invasive non-typhoidal Salmonella (iNTS)-GMMA vaccine: a first-in-human, randomised, dose escalation trial

Brama Hanumunthadu et al. EBioMedicine. 2025 Sep.

Abstract

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).

Keywords: Salmonella vaccine; iNTS.

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Conflict of interest statement

Declaration of interests ASS, CC, DDS, MB, MGA, OR, AMC, FBS, AKA, and RC are/were employees of GSK. OR, AMC, FBS, AKA, and RC hold financial equities in GSK. FBS received grants from BMGF. RC received support from EC Horizon for attending the meetings and/or travel, and is a member of the Steering Committees, together with other representatives of the Vacc-iNTS consortium partners, of the EC Horizon 2020 and the EDCTP grants awarded to the iNTS-GMMA vaccine project. BH received a VASE Travel Grant in 2022. MR is a principal investigator across multiple vaccine trials, a member of a DSMB and the JCVI. XL is a member of the DSMB across multiple trials, a clinical trial steering committee, the WHO SAGE Typhoid Working Group, and the WHO Technical Advisory Group for Salmonella Vaccines. MR and LG received support from the Horizon 2020 grant to attend meetings. The authors declare no other financial or non-financial relationships or activities. The Vacc-iNTS consortium was funded by the same grant funding the study. EU Framework Programme for Research and Innovation grant, Horizon 2020 (grant agreement number 815439).

Figures

Fig. 1
Fig. 1
CONSORT diagram.
Fig. 2
Fig. 2
Severity of solicited adverse reactions in days 0–7 after vaccination by study arm as self-reported in participant electronic diaries. a: Local reactions, first vaccination; b: Local reactions, second vaccination; c: Local reactions, third vaccination; d: Systemic reactions, first vaccination; e: Systemic reactions, second vaccination; f: Systemic reactions, third vaccination. Redness, hardness, and swelling gradings are derived from the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Grading of severity: Mild (Yellow), Moderate (Orange), Severe (Red). First Vaccination: placebo n = 12, lower dose n = 4, full dose n = 15. Second Vaccination: placebo n = 12, lower dose n = 3, full dose n = 15. Third Vaccination: placebo n = 11, lower dose n = 3, full dose n = 10.
Fig. 3
Fig. 3
Immune responses–geometric mean concentrations (±95% confidence interval) following vaccination by study arm and timepoint (day). a: Anti-SEn OAg IgG; b: Anti-STm OAg IgG; c: SBA responses against SEn; d: SBA responses against STm. Full dose: Day 0 (n = 15), 7 (n = 14), 28 (n = 15), 56 (n = 15), 63 (n = 13), 84 (n = 15), 168 (n = 12), 175 (n = 9), 196 (n = 12), 350 (n = 11); Lower dose: Day 0 (n = 4), 7 (n = 3), 28 (n = 4), 56 (n = 3), 63 (n = 3), 84 (n = 3), 168 (n = 3), 175 (n = 2), 196 (n = 3), 350 (n = 3); Placebo: Day 0 (n = 12), 7 (n = 12), 28 (n = 12), 56 (n = 12), 63 (n = 11), 84 (n = 12), 168 (n = 12), 175 (n = 10), 196 (n = 11), 350 (n = 11).
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