Improved CD4+ T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: A randomized trial
Improved CD4+ T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: A randomized trial
复制标题
DOI：
10.1016/j.vaccine.2012.05.035
复制
发表时间：
2013-04-19
期刊：
影响因子：
5.5
通讯作者：
Ofori-Anyinam, Opokua
中科院分区：
文献类型：
--
作者：
Leroux-Roels, Isabel;Forgus, Sheron;Ofori-Anyinam, Opokua
背景资料：卡介苗（BCG）结核病（TB）疫苗提供不完全保护，因此需要开发有效的结核病疫苗。Mtb 72 F/AS 02候选疫苗先前在纯化蛋白衍生物（PPD）阴性成人中显示出良好的临床耐受性和免疫原性。为了提高Mtb 72 F的稳定性，将点突变引入推定的丝氨酸蛋白酶位点以得到最终的M72构建体。AS 01是一种佐剂系统，与AS 02佐剂系统或无佐剂疫苗相比，可以潜在地改善体液和细胞免疫应答。本研究评价了含有40 μ g M72抗原与AS 02或AS 01的疫苗在Mtb初治成人中的安全性和免疫原性，并将结果与Mtb 72 F/AS 02疫苗进行了比较（40 μ g剂量），M72盐水溶液方法：在这项I/II期双盲对照试验中，110名参与者被随机分组，（4：4：1：1：1）接受M72/AS 01、M72/AS 02、Mtb 72 F/AS 02、M72/生理盐水或AS 01，按0、1个月时间表给药。对接受含佐剂M72疫苗的受试者进行随访，直至接种后3年。免疫反应和安全性/reactogenicity的评价performed.Results：对于所有疫苗，征集不良事件（AE）主要是轻度至中度和短暂的。未发生疫苗相关严重AE，无受试者因AE退出研究。Mtb 72 F和M72抗原与AS 02组合诱导的免疫应答相似。M72/AS 01和M72/AS 02诱导了稳健的多功能M72特异性CD 4（+）T细胞和抗体应答，持续3年，其中M72/AS 01的CD 4（+）T细胞应答最高。首次使用M72/AS 01和M72/AS 02进行的临床研究表明，两种疫苗均具有良好的临床耐受性，并诱导了高强度和持久的细胞毒性。介导和体液免疫应答。与M72/盐水对照相比，Mtb 72 F/AS 02和M72/AS 02疫苗具有显著更高的免疫应答。在测试的制剂中，M72/AS 01表现出显著更高的疫苗特异性Th 1 CD 4（+）T细胞应答，支持其进一步的临床评价。(C)2012爱思唯尔有限公司保留所有权利。
Background: The Bacille Calmette-Guerin (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-naive adults of vaccines containing 40 mu g of the M72 antigen with AS02 or AS01 and compared the results with Mtb72F/AS02 vaccine (40 mu g dose), M72 in saline (40 mu g dose) and AS01 alone.Methods: 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.Results: 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.Conclusion: 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. (C) 2012 Elsevier Ltd. All rights reserved.