The Jenner Institute, University of Oxford, Oxford, United Kingdom.
Department of Respiratory Science, University of Leicester, Leicester, United Kingdom.
Front Immunol. 2024 Nov 14;15:1427371. doi: 10.3389/fimmu.2024.1427371. eCollection 2024.
Tuberculosis (TB) is the leading cause of death worldwide from a single infectious agent. Bacillus Calmette-Guérin (BCG), the only licensed vaccine, provides limited protection. Controlled human infection models (CHIMs) are useful in accelerating vaccine development for pathogens with no correlates of protection; however, the need for prolonged treatment makes an unethical challenge agent. Aerosolised BCG provides a potential safe surrogate of infection. A CHIM in BCG-vaccinated as well as BCG-naïve individuals would allow identification of novel BCG-booster vaccine candidates and facilitate CHIM studies in populations with high TB endemicity. The purpose of this study was to evaluate the safety and utility of an aerosol BCG CHIM in historically BCG-vaccinated volunteers.
There were 12 healthy, historically BCG-vaccinated UK adults sequentially enrolled into dose-escalating groups. The first three received 1 × 10 CFU aerosol BCG Danish 1331 via a nebuliser. After safety review, subsequent groups received doses of 1 × 10 CFU, 1 × 10 CFU, or 1 × 10 CFU. Safety was monitored through self-reported adverse events (AEs), laboratory tests, and lung function testing. Immunology blood samples were taken pre-infection and at multiple timepoints post-infection. A bronchoalveolar lavage (BAL) taken 14 days post-infection was analysed for presence of live BCG.
No serious AEs occurred during the study. Solicited systemic and respiratory AEs were frequent in all groups, but generally short-lived and mild in severity. There was a trend for more reported AEs in the highest-dose group. No live BCG was detected in BAL from any volunteers. Aerosol BCG induced potent systemic cellular immune responses in the highest-dose group 7 days post-infection.
Aerosol BCG infection up to a dose of 1 × 10 CFU was well-tolerated in historically BCG-vaccinated healthy, UK adults. No live BCG was detected in the BAL fluid 14 days post-infection despite potent systemic responses, suggesting early clearance. Further work is needed to expand the number of volunteers receiving BCG via the aerosol route to refine and establish utility of this aerosol BCG CHIM.
https://clinicaltrials.gov/, identifier NCT04777721.
结核病（TB）是全球由单一感染源导致死亡的主要原因。卡介苗（BCG）是唯一获得许可的疫苗，但其提供的保护作用有限。受控人体感染模型（CHIM）可用于加速无保护相关因素的病原体疫苗的开发；然而，需要长期治疗使得其成为不道德的挑战制剂。雾化卡介苗为感染提供了一种潜在的安全替代物。在卡介苗接种和未接种卡介苗的个体中进行 CHIM，可鉴定新型卡介苗增强疫苗候选物，并促进高结核病流行地区的 CHIM 研究。本研究旨在评估历史上接种过卡介苗的志愿者中雾化卡介苗 CHIM 的安全性和实用性。
12 名健康的、历史上接种过卡介苗的英国成年人按剂量递增顺序纳入研究。前 3 名志愿者通过雾化器接受 1×10 CFU 雾化卡介苗丹麦 1331。在安全性审查后，后续志愿者分别接受 1×10 CFU、1×10 CFU 或 1×10 CFU 的剂量。通过自我报告的不良事件（AE）、实验室检测和肺功能检测来监测安全性。在感染前和感染后多个时间点采集免疫血液样本。在感染后 14 天进行支气管肺泡灌洗（BAL），分析活卡介苗的存在情况。
研究期间未发生严重不良事件。所有组均频繁出现有症状的全身性和呼吸道 AE，但通常为短暂且轻度。高剂量组报告的 AE 更多。任何志愿者的 BAL 中均未检测到活卡介苗。高剂量组在感染后 7 天，雾化卡介苗诱导了强烈的全身性细胞免疫反应。
在历史上接种过卡介苗的健康英国成年人中，高达 1×10 CFU 的雾化卡介苗感染耐受良好。尽管存在强烈的全身反应，但在感染后 14 天的 BAL 液中未检测到活卡介苗，表明其早期清除。需要进一步扩大通过气溶胶途径接受卡介苗的志愿者数量，以完善和确定该雾化卡介苗 CHIM 的实用性。
https://clinicaltrials.gov/，标识符 NCT04777721。
