Safety and immunogenicity of a conjugate vaccine candidate against Salmonella enterica serovars Typhi and Paratyphi A in healthy adults in Europe: a phase 1 randomised controlled trial

Background Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A remains a major concern. No vaccines are licensed against Salmonella Paratyphi A. We aimed to assess the safety and immunogenicity of an investigational conjugate vaccine against Salmonella Typhi and Paratyphi A (Vi-CRM 197 +O:2-CRM 197 ). Methods In this observer-masked, randomised, controlled, dose-escalation, single-centre, phase 1 trial done during Nov 28, 2022, to April 2, 2024, at the Centre for Evaluation of Vaccination in Belgium, healthy adults (aged 18–50 years) were randomly assigned (2:1 or 2:2:1 across different steps using sealed envelopes following a randomisation schedule generated by an independent statistician) to receive two intramuscular doses (on day 1 and day 169) of one of four Vi-CRM 197 +O:2-CRM 197 formulations (low dose or full dose, with or without aluminium hydroxide) or a control vaccine (Vi capsular polysaccharide vaccine and diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine for first and second dose). The primary outcome was vaccine safety (solicited events during 7 days and unsolicited adverse events during 28 days after vaccination, serious adverse events [SAEs], and adverse events or SAEs leading to study withdrawal or withholding of further study intervention administration from day 1 to day 197, and deviations from normal or baseline laboratory test values 7 days after vaccination). Secondary outcomes included long-term vaccine safety (SAEs and adverse events or SAEs leading to study withdrawal from day 197 to day 337), and immunogenicity, including anti-Vi and anti-O:2 IgG antibody geometric mean concentrations and geometric mean ratios (GMRs) by ELISA, and seroresponses (percentages of participants with anti-Vi IgG concentrations ≥4·3 μg/mL and ≥2·0 μg/mL; ≥4-fold anti-O:2 IgG concentration increase from baseline) at day 1 (as applicable), day 29, day 169, day 176, and day 197. Safety analyses were done on the solicited safety set, unsolicited safety set, and the exposed set. The primary immunogenicity analysis was done on the per-protocol set defined by timepoint. The trial is registered with ClinicalTrials.gov (NCT05613205) and gsk-studyregister.com (205480), and is completed. Findings 96 participants were randomly assigned, 12 to each low-dose group, 24 to each full-dose group, and 24 to the control group. The incidence of solicited administration-site events (mostly pain) ranged from six (50% [95% CI 21·1–78·9]) of 12 participants in the low-dose without aluminium hydroxide group to 23 (96% [78·9–99·9]) of 24 in the full-dose with aluminium hydroxide group, versus 22 (92% [73·0–99·0]) of 24 in the control group. Solicited systemic events (mostly fatigue, headache, and myalgia) ranged from eight (67% [34·9–90·1]) of 12 in the low-dose groups to 20 (83% [62·6–95·3]) of 24 in the full-dose with aluminium hydroxide group, versus 21 (88% [67·6–97·3]) of 24 in the control group. The incidence of unsolicited adverse events (mostly nasopharyngitis) ranged from seven (58% [27·7–84·8]) of 12 in the low-dose without aluminium hydroxide group to ten (83% [51·6–97·9]) of 12 in the low-dose with aluminium hydroxide group, versus 14 (58% [36·6–77·9]) of 24 in the control group. Most safety laboratory results were within reference ranges. No SAEs occurred. After dose 1 (ie, at day 29), full-dose without aluminium hydroxide and full-dose with aluminium hydroxide induced the highest anti-Vi IgG responses (GMR 53·01 [95% CI 31·94–87·99] and 31·55 [18·74–53·11], respectively) versus control (4·50 [2·93–6·90]). Full-dose without aluminium hydroxide and low-dose without aluminium hydroxide induced the highest anti-O:2 IgG responses after dose 1 (GMR 162·61 [91·17–290·04] and 114·19 [44·83–290·86], respectively), versus control (1·27 [1·02–1·60]). 89–100% and 82–100% of participants (lowest percentages for low-dose with aluminium hydroxide) had anti-Vi IgG ≥4·3 μg/mL at day 29 (in initially seronegative participants) and ≥4-fold anti-O:2 IgG increase from baseline, respectively, versus 13 (54% [95% CI 32·8–74·4]) and one (4% [0·1–21·1]) of 24 participants in the control group, respectively. The second dose did not boost the responses. Interpretation Vi-CRM 197 +O:2-CRM 197 formulations did not raise safety concerns and showed immunogenicity with a single dose, supporting further clinical assessment of the full-dose without aluminium hydroxide in target populations (infants and older age groups) in endemic regions. Funding Wellcome Trust.