Efficacy and safety of VPM1002 and Immuvac in preventing tuberculosis: phase 3 randomised clinical trial (PreVenTB trial).

Methods

Phase 3 randomised clinical trial (PreVenTB trial).

III期随机临床试验（PreVenTB试验）。

18 sites across six states of India.

位于印度六个州的18个地点。

12 717 healthy household contacts (aged ≥6 years) of patients with a smear positive TB test.

12,717名年龄≥6岁的患者涂片阳性结核病检测的健康家庭接触者。

Participants were randomly assigned in a 1:1:1 ratio (using block randomisation with variable sample size) to receive an intradermal injection of VPM1002, Immuvac, or placebo in both arms.

参与者以1:1:1的比例（使用具有可变样本大小的分块随机化）被随机分配接受VPM1002、Immuvac或安慰剂的皮内注射，双臂均进行。

After one month, a second dose was administered in one arm to 11 829 healthy participants.

一个月后，一个臂中的11 829名健康参与者接受了第二剂注射。

outcome_measures

The primary outcome was efficacy against confirmed TB (pulmonary TB and extrapulmonary TB) over 38 months of follow-up.

主要结果是38个月随访期间对确诊结核病（肺结核和肺外结核）的疗效。

Secondary outcomes were development of latent TB infection, adverse and serious adverse events, efficacy in predefined age groups, and immunogenicity.

次要结果包括潜伏性结核感染的发展、不良和严重不良事件、预定义年龄组的疗效以及免疫原性。

Exploratory outcomes were efficacy when considering tuberculin skin test status, and post hoc analyses of efficacy in participants aged 6-14 and according to body mass index.

探索性结果考虑了结核菌素皮肤试验状态下的疗效，并对6-14岁参与者以及根据体重指数的疗效进行了事后分析。

Results

252 and 227 participants developed microbiologically confirmed TB in modified intention-to-treatand per protocol groups, respectively.

在修改意向治疗组和按方案组中，分别有252名和227名参与者发展为微生物学证实的结核病。

The per protocol analysis showed 65 (1.68%), 80 (2.09%), and 82 (2.13%) participants developed TB in the VPM1002, Immuvac, and placebo groups, respectively.

按方案分析显示，VPM1002组、Immuvac组和安慰剂组分别有65人（1.68%）、80人（2.09%）和82人（2.13%）发展为结核病（TB）。

Of these, 12 (0.31%), 16 (0.42%), and 24 (0.62%) developed extrapulmonary TB in the VPM1002, Immuvac, and placebo groups, respectively.

在这些病例中，VPM1002组、Immuvac组和安慰剂组分别有12人（0.31%）、16人（0.42%）和24人（0.62%）发展为肺外结核。

In the per protocol analysis, VPM1002 showed vaccine efficacy of 21.4% (95% confidence interval(CI) -8.9% to 43.2%), 19.5% (-14.6% to 43.4%), and 50.4% (0.8% to 75.2%) against all TB, pulmonary TB, and extrapulmonary TB, respectively.

在按方案分析中，VPM1002对所有结核病、肺结核和肺外结核的疫苗效力分别为21.4%（95%置信区间（CI）-8.9%至43.2%）、19.5%（-14.6%至43.4%）和50.4%（0.8%至75.2%）。

Immuvac showed vaccine efficacy of 33.2% (-25.9% to 64.5%) against extrapulmonary TB.

Immuvac对肺外结核的疫苗效力为33.2%（-25.9%至64.5%）。

VPM1002 and Immuvac showed vaccine efficacy of 64.9% (-2% to 90.1%) and 66.3% (1.9% to 90.5%) against extrapulmonary TB in participants with tuberculin skin test positivity.

VPM1002 和 Immuvac 在结核菌素皮肤试验阳性的参与者中对肺外结核的疫苗保护效力分别为 64.9%（-2% 至 90.1%）和 66.3%（1.9% 至 90.5%）。

Both vaccines were well tolerated with mild local reactions in about a third of participants.

两种疫苗均具有良好的耐受性，约三分之一的参与者出现了轻微的局部反应。

VPM1002 and Immuvac induced Mycobacterium tuberculosis specific polyfunctional CD4+ T cells.

VPM1002和Immuvac诱导了针对结核分枝杆菌特异性的多功能CD4+ T细胞。

Post hoc analyses showed vaccine efficacy of 64.6% (95% CI 16.3% to 85.1%) against all forms of TB, 62.1% (3.0% to 85.2%) against pulmonary TB, and 77.6% (-3.7% to 95.2%) against extrapulmonary TB in participants aged 6-14 years in the VPM1002 group.

事后分析显示，在6-14岁的VPM1002组参与者中，疫苗对所有形式的结核病的效力为64.6%（95% 置信区间16.3%至85.1%），对肺结核的效力为62.1%（3.0%至85.2%），对外周结核的效力为77.6%（-3.7%至95.2%）。

Conclusions

Both vaccines were safe but did not show any efficacy against all forms of microbiologically confirmed TB or pulmonary TB.

两种疫苗均安全，但对所有形式的微生物学证实的结核病或肺结核均未显示出任何疗效。

VPM1002 showed considerable efficacy against extrapulmonary TB.

VPM1002对肺外结核显示出相当的疗效。

Both vaccines showed efficacy against extrapulmonary TB in participants who had a positive tuberculin skin test.

两种疫苗均显示出对结核菌素皮肤试验阳性的参与者中肺外结核的有效性。

trial_registration

Clinical Trials Registry India CTRI/2019/01/017026.

印度临床试验注册处 CTRI/2019/01/017026。