Safety and immunogenicity of a recombinant M2e-flagellin influenza vaccine (STF2.4xM2e) in healthy adults
Safety and immunogenicity of a recombinant M2e-flagellin influenza vaccine (STF2.4xM2e) in healthy adults
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DOI：
10.1016/j.vaccine.2011.05.041
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发表时间：
2011-07-18
期刊：
影响因子：
5.5
通讯作者：
Shaw, Alan
中科院分区：
文献类型：
--
作者：
Turley, Christine B.;Rupp, Richard E.;Shaw, Alan
背景资料：基质蛋白2（M2 e）的胞外域是广泛保护性甲型流感疫苗的有希望的候选者，因为其高度保守并且针对M2 e的抗体在动物模型中具有保护性。STF2.4xM2e（VAX 102）是一种重组融合蛋白，将M2 e抗原的四个串联拷贝连接到鼠伤寒沙门氏菌鞭毛蛋白（一种用作佐剂的TLR 5配体）。这项首次人体试验的目的是评估VAX 102作为初免-加强方案给予健康成人的安全性和免疫原性。方法：60名18-49岁的受试者参加了一项多中心、双盲、随机、安慰剂对照试验（研究1）。基于临床前数据，初始设计包括从10 μ g开始的剂量，以及递增计划。在10 μ g剂量下观察到反应原性后，重新设计试验以评价0.3、1.0和3 μ g剂量。本研究后，16例受试者入组研究2，这是一项开放标签、低剂量研究，以评价0.03和0.1 μ g的剂量。在这两项试验中，疫苗或安慰剂均通过肌肉注射（i.m.）在0和28天。在免疫后1天和7天进行临床和实验室安全性评估。在每次给药后7、14和28天通过ELISA评估对M2 e和鞭毛蛋白的免疫应答。血清转化定义为血清IgG抗-M2 e抗体值>= 0.174 μ g/ml和浓度升高4倍。结果：0.03-1 μ g的剂量在所有受试者中均安全且耐受良好。在第二剂疫苗后，0.03和0.1 μ g剂量产生有限的免疫原性（分别为38%和75%）。0.3和1.0 μ g剂量在第一剂后24名接种者中有18名（75%）具有免疫原性，第二剂后23名（96%）具有免疫原性。在1.0 μ g组中，首次给药后M2 e抗体浓度的几何平均值为0.4 μ g/ml，加强给药后为1.7 μ g/ml。在较高剂量下，M2 e抗体浓度和血清转换率无显著差异（p > 0.05）。对鞭毛蛋白的免疫应答是稳健的，但在加强剂量后似乎不干扰M2 e抗体应答。在首次注射较高剂量（3和10 μ g）的VAX 102后，在一些受试者中观察到自限性但严重的症状，并与C反应蛋白水平升高相关。虽然没有直接测量，这种反应被认为是介导的细胞因子release.Conclusions：VAX 102是安全的，并诱导高抗体水平的M2 e在0.3和1.0 μ g剂量。TLR 5配体S.鼠伤寒沙门氏菌鞭毛蛋白是一种通过激活先天性免疫来获得免疫样活性的新方法，并且当与M2 e蛋白的多个拷贝融合时，该疫苗能够诱导人体中针对流感病毒的先前非免疫原性、高度保守部分的抗体增加四倍。M2 e抗体在人体中可能提供的保护的临床相关性是未来研究的重点。(C)2011爱思唯尔有限公司版权所有。
Background: The ectodomain of matrix protein 2 (M2e) is a promising candidate for a broadly protective influenza A vaccine because it is highly conserved and antibodies to M2e are protective in animal models. STF2.4xM2e (VAX102) is a recombinant fusion protein that links four tandem copies of the M2e antigen to Salmonella typhimurium flagellin, a TLR5 ligand used as an adjuvant. The objectives of this first-in-human study were to assess the safety and immunogenicity of VAX102 given as a prime-boost regimen to healthy adults.Methods: Sixty subjects 18-49 years old were enrolled in a multicenter, double-blind, randomized, placebo-controlled trial (Study 1). Based on pre-clincial data, initial design included doses starting at 10 mu g, with an escalation plan. After reactogenicity was noted at the 10 mu g dose, the trial was redesigned to evaluate 0.3, 1.0, and 3 mu g doses. Following this study, 16 subjects were enrolled in Study 2, an open label, low dose study, to evaluate doses of 0.03 and 0.1 mu g. In both trials, vaccine or placebo was given intramuscularly (i.m.) at 0 and 28 days. Clinical and laboratory safety assessments took place 1 and 7 days after immunization. Immune responses to M2e and flagellin were assessed by ELISA at 7, 14 and 28 days after each dose. Seroconversion was defined as a serum IgG anti-M2e antibody value >= 0.174 mu g/ml and a fourfold rise in concentration.Results: Doses of 0.03-1 mu g were safe and well tolerated in all subjects. Doses of 0.03 and 0.1 mu g produced limited immunogenicity (38% and 75% respectively), after the second dose of vaccine. Doses of 0.3 and 1.0 mu g were immunogenic in 18 (75%) of 24 vaccinees after the first dose and 23 (96%) after the second dose. In the 1.0 mu g group, the geometric mean M2e antibody concentration was 0.4 mu g/ml after the first dose and 1.7 mu g/ml after the booster dose. M2e antibody concentrations and seroconversion rates were not significantly different at higher doses (p > 0.05). Immune response to flagellin was robust but did not appear to interfere with M2e antibody responses after the booster dose. Following the first injection of VAX102 at higher doses (3 and 10 mu g), self-limited but severe symptoms were noted in some subjects and were associated with elevated levels of C-reactive protein. Although not directly measured, this reaction was believed to be mediated by cytokine release.Conclusions: VAX102 was safe and induced high antibody levels to M2e at 0.3 and 1.0 mu g doses. The TLR5 ligand, S. typhimurium flagellin, is a novel approach to adjuvant-like activity through activation of innate immunity, and when fused to multiple copies of the M2e protein, the vaccine was able to induce a fourfold rise in antibody in humans, to a previously non-immunogenic, highly-conserved portion of the influenza virus. Clinical correlates of protection that may be afforded by M2e antibody in humans are a future focus of investigation. (C) 2011 Elsevier Ltd. All rights reserved.