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

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-09-01 Epub Date: 2025-09-03 DOI:10.1016/j.ebiom.2025.105903

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

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引用次数: 0

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).

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侵袭性非伤寒沙门氏菌(iNTS)-GMMA疫苗的安全性和免疫原性：一项首次人体随机剂量递增试验

背景：侵袭性非伤寒沙门氏菌（iNTS）是撒哈拉以南非洲发病率和死亡率的主要原因。我们评估了一种外膜囊泡疫苗（tts - gmma）的安全性和免疫原性，该疫苗来源于两种最常见的血清型，肠炎沙门氏菌（SEn）和鼠伤寒沙门氏菌（STm）。方法：该单中心、随机队列、安慰剂对照剂量递增单盲与盲法评估试验纳入年龄在18-55岁的健康人群，符合方案入选标准。在牛津大学CCVTM，前哨队列（1组）按1:1随机分配到低剂量（10.6 μg总o抗原[OAg]）或安慰剂，随后的队列按1:1随机分配到全剂量（40 μg总OAg）或安慰剂（2组），最后一个队列按2:1随机分配到全剂量（40 μg总OAg）或安慰剂。参与者在0、2和6个月时接受了三次肌肉内注射。草案号2020-000510-14。研究结果：在2022年5月至11月期间，7名参与者被分配到第1组，6名参与者被分配到第2组，18名参与者被分配到第3组。26/31在12个月时完成随访。未报告发生ssa或susar。最常见的不良事件（AE）是注射部位反应。tts - gmma组的所有参与者（19/19,100%）都报告了至少一次征求性不良事件，其严重程度大多为轻度至中度。接种疫苗后28天，至少可能与tts - gmma相关的主动不良事件以轻度（6.50%）和中度（4.33.3%）为主。与安慰剂（SEn: 73.7 [22.4, 242.3]; STm: 41.1[17.6, 95.5]）相比，全剂量组血清特异性OAg IgG水平在第28天达到峰值（SEn: GMC 865.4 [95% CI 404.9, 1849.6]; STm: 833.2[401.8, 1727.9]）。血清杀菌抗体（SBA）在首次接种后第28天达到峰值（SEn: 38,722.7 [14,209, 105,528.1]; STm: 29,989[18,528.6, 48,537.9]），而安慰剂组（SEn: 9976 [4261.1, 23,355.5]; STm: 6694.3[2742, 16,343.6]）。解释：ts - gmma疫苗具有免疫原性，没有显示出妨碍进一步开发的安全性问题，支持进一步进行I期和II期临床试验。资助：欧盟研究与创新框架计划资助，地平线2020（资助协议号815439）。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.