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新型抗结核疫苗RUTI的安全性、耐受性和免疫原性：潜伏性结核感染患者的随机、安慰剂对照II期临床试验

Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection.

作者信息

Nell Andre S, D'lom Eva, Bouic Patrick, Sabaté Montserrat, Bosser Ramon, Picas Jordi, Amat Mercè, Churchyard Gavin, Cardona Pere-Joan

机构信息

PAREXEL Early Phase Clinical Unit, Bloemfontein, South Africa.

PAREXEL International, Madrid, Spain.

出版信息

PLoS One. 2014 Feb 26;9(2):e89612. doi: 10.1371/journal.pone.0089612. eCollection 2014.

DOI:10.1371/journal.pone.0089612
PMID:24586912
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3935928/
Abstract

OBJECTIVES: To evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection. METHODS AND FINDINGS: Double-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV-) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/-): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV- status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation. CONCLUSION: This Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future trials, preceded by an extended safety clinical phase. TRIAL REGISTRATION: ClinicalTrials.gov NCT01136161.

摘要

目的：在潜伏性结核感染受试者中，评估三种不同剂量（5、25和50微克）的新型抗结核疫苗RUTI与安慰剂相比的安全性、耐受性和免疫原性。 方法与结果：双盲、随机、安慰剂对照的II期临床试验（95例患者随机分组）。在完成为期一个月的异烟肼（INH）预接种后，对三种不同剂量的RUTI和安慰剂进行测试，将HIV阳性（n = 47）和HIV阴性受试者（n = 48）随机分组。每位受试者接受两次疫苗接种，间隔28天。5例患者退出，90例患者完成研究。安全性评估显示研究期间无死亡病例。两名受试者出现严重不良事件，一名在服用INH时发生视网膜脱离，未参与随机分组，另一名双臂各出现一处严重的局部注射部位脓肿并住院治疗；因果关系评估为极有可能，到研究结束时该结果已得到缓解。除安慰剂组的5例（21%）患者（3例HIV阳性和2例HIV阴性）外，所有患者在研究期间均报告至少发生一次不良事件（AE）。RUTI接种者中最常出现的AE（HIV阳性/阴性中的百分比）为：注射部位反应[红斑（91/92）、硬结（94/92）、局部结节（46/25）、局部疼痛（66/75）、无菌脓肿（6/6）、肿胀（74/83）、溃疡（20/11）、头痛（17/22）和鼻咽炎（20/5）]。这些事件大多为轻度且耐受性良好。总体而言，观察到了多抗原反应，其因HIV状态而异。给予25微克RUTI时获得了最佳的多抗原反应，尤其是在HIV阳性受试者中，第二次接种后反应未增强。 结论：这项II期临床试验证明了RUTI具有合理的耐受性。RUTI疫苗在潜伏性结核感染受试者中的免疫原性特征，即使在各亚组中有所不同，也使我们考虑在未来试验中先进行一个延长的安全性临床阶段，然后单次注射最高剂量之一。 试验注册：ClinicalTrials.gov NCT01136161。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/a07ec62b3bf1/pone.0089612.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/6e538f773c03/pone.0089612.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/35980466c832/pone.0089612.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/6abcd9d42f32/pone.0089612.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/a07ec62b3bf1/pone.0089612.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/6e538f773c03/pone.0089612.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/35980466c832/pone.0089612.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/6abcd9d42f32/pone.0089612.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0052/3935928/a07ec62b3bf1/pone.0089612.g004.jpg

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