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Preclinical study and phase I clinical safety evaluation of recombinant Mycobacterium tuberculosis ESAT6 protein

机译：重组结核分枝杆菌ESAT6蛋白的临床前研究和I期临床安全性评估

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Background To investigate the ability of rESAT6 to identify different mycobacteria-sensitized guinea pigs and its safety in preclinical and phase I clinical study. Material and Methods Guinea pigs were sensitized with different Mycobacteria. After sensitization, all animals were intradermally injected with rESAT6 and either PPD or PPD-B. At 24 h after the injection, the erythema of the injection sites were measured using a double-blind method. For the preclinical safety study, different doses of rESAT6 and BSA were given 3 times intramuscularly to guinea pigs. On day 14 after the final immunization, the guinea pigs were intravenously injected with the same reagents in the hind legs and the allergic reactions were observed. A single-center, randomized, open phase I clinical trial was employed. The skin test was conducted in 32 healthy volunteers aged 19–65 years with 0.1 μg, 0.5 μg, and 1 μg rESAT6. Physical examination and laboratory tests were performed before and after the skin test and adverse reactions were monitored. The volunteers’ local and systemic adverse reactions and adverse events were recorded for 7 days. Results Positive PPD or PPD-B skin tests were observed in all Mycobacteria-sensitized guinea pigs; the diameters of erythema were all >10 mm. The rESAT6 protein induced a positive skin test result in the guinea pigs sensitized with MTB, M. bovis, M. africanum and M. kansasii; the diameters of erythema were 14.7±2.0, 9.3±3.8, 18.7±2.4, and 14.8±4.2 mm, respectively. A negative skin test result was detected in BCG-vaccinated and other NTM-sensitized guinea pigs. The rESAT6 caused no allergic symptoms, but many allergic reactions, such as cough, dyspnea, and even death, were observed in the guinea pigs who were administered BSA. During the phase I clinical trial, no adverse reactions were found in the 0.1 μg rESAT6 group, but in the 0.5 μg rESAT6 group 2 volunteers reported pain and 1 reported itching, and in the 1 μg rESAT6 group there was 1 case of pain, 1 case of itching, and 1 case of blister. No other local or systemic adverse reactions or events were reported. Conclusions The rESAT6 can differentiate effectively among MTB infection, BCG vaccination, and NTM infection and is safe in healthy volunteers.
机译：背景研究rESAT6鉴定不同分枝杆菌致敏豚鼠的能力及其在临床前和I期临床研究中的安全性。材料和方法用不同的分枝杆菌敏化豚鼠。致敏后，向所有动物皮内注射rESAT6和PPD或PPD-B。在注射后24小时，使用双盲方法测量注射部位的红斑。为了进行临床前安全性研究，对豚鼠肌肉注射3次不同剂量的rESAT6和BSA。最终免疫后第14天，对豚鼠在后腿静脉注射相同的试剂，并观察到过敏反应。采用了单中心，随机，开放式I期临床试验。皮肤测试是在32位19-65岁的健康志愿者中分别使用0.1μg，0.5μg和1μgrESAT6进行的。在皮肤测试之前和之后进行身体检查和实验室测试，并监测不良反应。记录志愿者7天的局部和全身不良反应和不良事件。结果在所有分枝杆菌致敏的豚鼠中，PPD或PPD-B皮肤试验均呈阳性。红斑直径均> 10 mm。 rESAT6蛋白在用MTB，牛分枝杆菌，非洲分枝杆菌和堪萨斯分枝杆菌致敏的豚鼠中引起皮肤试验阳性结果。红斑直径分别为14.7±2.0、9.3±3.8、18.7±2.4和14.8±4.2 mm。在接种了BCG的疫苗和其他NTM致敏的豚鼠中，皮肤测试结果为阴性。 rESAT6没有引起过敏症状，但是在给予BSA的豚鼠中观察到了许多过敏反应，例如咳嗽，呼吸困难甚至死亡。在I期临床试验期间，在0.1μgrESAT6组中未发现不良反应，但在0.5μgrESAT6组中，有2名志愿者报告了疼痛，有1名报告了瘙痒，在1μgrESAT6组中，有1例疼痛，1例疼痛。 1例瘙痒和1例水泡。没有其他局部或全身不良反应或事件的报道。结论rESAT6能有效区分MTB感染，BCG疫苗接种和NTM感染，对健康志愿者是安全的。

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