Safety and immunogenicity of the invasive non-typhoidal Salmonella (iNTS)-GMMA vaccine: a first-in-human, randomised, dose escalation trial
Brama Hanumunthadu, Tesfaye Demissie, Melanie Greenland, Peter Skidmore, Kiarash Tanha, Tim Crocker-Buqué, Nelly Owino, Antonella Silvia Sciré, Chiara Crispino, Daniele De Simone, Marta Benincasa, Maria Grazia Aruta, Omar Rossi, Anna Colucci, Francesco Berlanda Scorza, Ashwani Kumar Arora, Xinxue Liu, Elizabeth Clutterbuck, Leila Godfrey, Rocı́o Canals, Maheshi Ramasamy, Francis Agyapong, Gianluca Breghi, Annalisa Ciabattini, John A. Crump, Melita A. Gordon, Liselotte Hardy, Samuel Kariuki, Stefano Malvolti, Carsten Mantel, Christian S. Marchello, Florian Marks, Donata Medaglini, Tonney S. Nyirenda, Mercy Ngetich, Ellis Owusu‐Dabo, Francesco Santoro, J. Anthony G. Scott, Bassiahi Abdramane Soura, Tiziana Spadafina, Bieke Tack
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).