Safety, Tolerability, and Immunogenicity of the Novel Antituberculous Vaccine RUTI: Randomized, Placebo-Controlled Phase II Clinical Trial in Patients with Latent Tuberculosis Infection

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

研究目标
评估三种不同剂量（5、25和50 µg）的新型抗结核疫苗RUTI与安慰剂相比，在潜伏性结核感染（latent tuberculosis infection, LTBI）受试者中的安全性、耐受性与免疫原性。

研究方法与结果
本研究为双盲、随机、安慰剂对照II期临床试验，共纳入95例随机化受试者。在完成1个月异烟肼（isoniazid, INH）预治疗后，分别在HIV阳性（n=47）与HIV阴性（n=48）受试者中测试三种RUTI剂量及安慰剂。每位受试者接受2剂疫苗接种，间隔28天。共有5例受试者退出研究，90例完成本试验。
安全性评估显示，研究期间无死亡病例发生。2例受试者出现严重不良事件：1例在服用异烟肼期间发生视网膜脱离，未被随机入组；另1例双臂均出现严重注射部位脓肿并住院治疗，其因果关系被评估为极有可能相关，至研究结束时该不良事件已完全缓解。除安慰剂组的5例受试者（占比21%，其中HIV阳性3例、HIV阴性2例）外，所有受试者在研究期间均报告至少1次不良事件（adverse event, AE）。
RUTI接种者中最常见的不良事件：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）、无菌性脓肿（6/6）、肿胀（74/83）、溃疡（20/11）、头痛（17/22）及鼻咽炎（20/5）]。上述不良事件大多为轻度，且耐受性良好。整体而言，本研究观察到多抗原免疫应答反应，该应答因HIV感染状态存在差异。接种25 µg RUTI时可获得最佳多抗原应答效果，尤其在HIV阳性受试者中，且第2剂接种后应答未进一步增强。

研究结论
本项II期临床试验证实RUTI具有良好的耐受性。尽管不同组别间免疫原性存在差异，但RUTI疫苗在潜伏性结核感染受试者中展现出可接受的免疫原性特征，提示未来可先开展扩大安全性的临床研究阶段，再尝试单次接种最高剂量疫苗中的一种。

试验注册
ClinicalTrials.gov NCT01136161