Hoft Daniel F, Blazevic Azra, Selimovic Asmir, Turan Aldin, Tennant Jan, Abate Getahun, Fulkerson John, Zak Daniel E, Walker Robert, McClain Bruce, Sadoff Jerry, Scott Judy, Shepherd Barbara, Ishmukhamedov Jasur, Hokey David A, Dheenadhayalan Veerabadran, Shankar Smitha, Amon Lynn, Navarro Garnet, Podyminogin Rebecca, Aderem Alan, Barker Lew, Brennan Michael, Wallis Robert S, Gershon Anne A, Gershon Michael D, Steinberg Sharon
Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States.
Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States.
EBioMedicine. 2016 May;7:278-86. doi: 10.1016/j.ebiom.2016.04.010. Epub 2016 Apr 19.
We report a first-in-human trial evaluating safety and immunogenicity of a recombinant BCG, AERAS-422, over-expressing TB antigens Ag85A, Ag85B, and Rv3407 and expressing mutant perfringolysin.
This was a randomized, double-blind, dose-escalation trial in HIV-negative, healthy adult, BCG-naïve volunteers, negative for prior exposure to Mtb, at one US clinical site. Volunteers were randomized 2:1 at each dose level to receive a single intradermal dose of AERAS-422 (>10(5)-<10(6)CFU=low dose, ≥10(6)-<10(7)CFU=high dose) or non-recombinant Tice BCG (1-8×10(5)CFU). Randomization used an independently prepared randomly generated sequence of treatment assignments. The primary and secondary outcomes were safety and immunogenicity, respectively, assessed in all participants through 182days post-vaccination. ClinicalTrials.gov registration number: NCT01340820.
Between Nov 2010 and Aug 2011, 24 volunteers were enrolled (AERAS-422 high dose, n=8; AERAS-422 low dose, n=8; Tice BCG, n=8); all were included in the safety and immunogenicity analyses. All 24 subjects had at least one adverse event, primarily expected local reactions. High dose AERAS-422 vaccination induced Ag85A- and Ag85B-specific lymphoproliferative responses and marked anti-mycobacterial activity in a whole blood bactericidal activity culture assay (WBA), but was associated with varicella zoster virus (VZV) reactivation in two vaccinees. These volunteers displayed high BCG-specific IFN-γ responses pre- and post-vaccination possibly predisposing them to autocrine/paracrine negative regulation of immune control of latent VZV. A systems biology transcriptomal approach identified positive correlations between post-vaccination T cell expression modules and WBA, and negative correlations between post-vaccination monocyte expression modules and WBA. The expression of one key macrophage marker (F4/80) was constitutively elevated in the two volunteers with zoster.
The unexpected development of VZV in two of eight healthy adult vaccine recipients resulted in discontinuation of AERAS-422 vaccine development. Immunological and transcriptomal data identified correlations with the development of TB immunity and VZV that require further investigation.
Aeras, FDA, Bill and Melinda Gates Foundation.
我们报告了一项首次人体试验，评估重组卡介苗AERAS - 422的安全性和免疫原性，该重组卡介苗过表达结核杆菌抗原Ag85A、Ag85B和Rv3407，并表达突变型产气荚膜梭菌溶血素。
这是一项在美国一个临床地点进行的随机、双盲、剂量递增试验，受试者为未感染HIV的健康成年初种卡介苗志愿者，既往未接触过结核分枝杆菌。在每个剂量水平，志愿者按2:1随机分组，分别接受单次皮内注射AERAS - 422（>10⁵ - <10⁶CFU = 低剂量，≥10⁶ - <10⁷CFU = 高剂量）或非重组Tice卡介苗（1 - 8×10⁵CFU）。随机分组使用独立编制的随机生成的治疗分配序列。主要和次要结局分别为安全性和免疫原性，在所有参与者接种疫苗后182天进行评估。ClinicalTrials.gov注册号：NCT01340820。
2010年11月至2011年8月，共招募了24名志愿者（AERAS - 422高剂量组，n = 8；AERAS - 422低剂量组，n = 8；Tice卡介苗组，n = 8）；所有志愿者均纳入安全性和免疫原性分析。24名受试者均至少发生一次不良事件，主要为预期的局部反应。高剂量AERAS - 422疫苗接种诱导了Ag85A和Ag85B特异性淋巴细胞增殖反应，并在全血杀菌活性培养试验（WBA）中表现出显著的抗分枝杆菌活性，但有两名接种者出现了水痘带状疱疹病毒（VZV）再激活。这些志愿者在接种疫苗前后均表现出高卡介苗特异性IFN - γ反应，这可能使他们易受潜伏性VZV免疫控制的自分泌/旁分泌负调节影响。一种系统生物学转录组学方法确定了接种疫苗后T细胞表达模块与WBA之间的正相关，以及接种疫苗后单核细胞表达模块与WBA之间的负相关。两名患带状疱疹的志愿者中一种关键巨噬细胞标志物（F4/80）的表达持续升高。
8名健康成年疫苗接种者中有2人意外发生VZV感染，导致AERAS - 422疫苗研发终止。免疫学和转录组学数据确定了与结核免疫和VZV感染发生的相关性，需要进一步研究。
Aeras、美国食品药品监督管理局、比尔及梅琳达·盖茨基金会。
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