Center for Vaccinology, Ghent University Hospital, Ghent, Belgium.
Vaccine. 2013 Apr 19;31(17):2196-206. doi: 10.1016/j.vaccine.2012.05.035. Epub 2012 May 27.
The Bacille Calmette-Guérin (BCG) tuberculosis (TB) vaccine provides incomplete protection, necessitating development of an effective vaccine against TB disease. The Mtb72F/AS02 candidate vaccine was previously shown to be clinically well tolerated and immunogenic in Purified Protein Derivative (PPD)-negative adults. To improve the stability of Mtb72F, a point mutation was introduced into a putative serine protease site to give the final M72 construct. AS01 is an Adjuvant System that can potentially improve both humoral and cellular immune responses compared to the AS02 Adjuvant System or unadjuvanted vaccine. This study evaluated the safety and immunogenicity in Mtb-naïve adults of vaccines containing 40 μg of the M72 antigen with AS02 or AS01 and compared the results with Mtb72F/AS02 vaccine (40 μg dose), M72 in saline (40 μg dose) and AS01 alone.
In this Phase I/II observer-blind controlled trial, 110 participants were randomized (4:4:1:1:1) to receive M72/AS01, M72/AS02, Mtb72F/AS02, M72/saline or AS01, following a 0, 1-month schedule. Subjects receiving the adjuvanted M72 vaccines were followed up until 3 years post vaccination. Evaluation of the immune response and safety/reactogenicity was performed.
For all vaccines, solicited adverse events (AEs) were predominantly mild to moderate and transient. No vaccine-related serious AEs occurred and no subject withdrew due to an AE. Immune responses induced by Mtb72F and M72 antigens combined with AS02 were similar. M72/AS01 and M72/AS02 induced robust polyfunctional M72-specific CD4(+) T cell and antibody responses persisting at 3 years, with the highest CD4(+) T cell responses found with M72/AS01.
This first clinical study with M72/AS01 and M72/AS02 showed that both vaccines were clinically well tolerated and induced high magnitude and persistent cell-mediated and humoral immune responses. The Mtb72F/AS02 and M72/AS02 vaccines were comparably immunogenic with significantly higher immune responses compared to the M72/saline control. Of the formulations tested, M72/AS01 demonstrated significantly higher vaccine specific Th1 CD4(+) T cell responses supporting its further clinical evaluation.
卡介苗（BCG）结核疫苗提供不完全保护，需要开发有效的结核疾病疫苗。先前已显示 Mtb72F/AS02 候选疫苗在 PPD 阴性成人中具有良好的临床耐受性和免疫原性。为了提高 Mtb72F 的稳定性，在假定的丝氨酸蛋白酶位点引入了一个点突变，得到最终的 M72 构建体。AS01 是一种佐剂系统，与 AS02 佐剂系统或未佐剂疫苗相比，有可能改善体液和细胞免疫应答。本研究评估了含有 40 μg M72 抗原的疫苗在结核-naive 成人中的安全性和免疫原性，该疫苗含有 AS02 或 AS01，并将结果与 Mtb72F/AS02 疫苗（40 μg 剂量）、M72 生理盐水（40 μg 剂量）和 AS01 进行比较。
在这项 I/II 期观察者盲对照试验中，110 名参与者按照 4:4:1:1:1 的比例随机分配（M72/AS01、M72/AS02、Mtb72F/AS02、M72/生理盐水或 AS01），采用 0、1 个月的方案。接受佐剂 M72 疫苗的受试者随访至接种后 3 年。评估免疫应答和安全性/反应原性。
对于所有疫苗，预期的不良事件（AE）主要为轻度至中度和短暂。没有疫苗相关的严重 AE 发生，也没有受试者因 AE 退出。与 AS02 联合使用 Mtb72F 和 M72 抗原诱导的免疫应答相似。M72/AS01 和 M72/AS02 诱导了强大的多效性 M72 特异性 CD4+T 细胞和抗体应答，持续 3 年，其中 M72/AS01 诱导的 CD4+T 细胞应答最高。
这是第一项关于 M72/AS01 和 M72/AS02 的临床研究表明，两种疫苗均具有良好的临床耐受性，并诱导了高幅度和持久的细胞介导和体液免疫应答。与 M72/生理盐水对照相比，Mtb72F/AS02 和 M72/AS02 疫苗具有相当的免疫原性，且免疫应答显著更高。在测试的制剂中，M72/AS01 显示出更高的疫苗特异性 Th1 CD4+T 细胞应答，支持其进一步的临床评估。
