Viroscience Lab, Erasmus Medical Center, Rotterdam, Netherlands.
Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University of Munich, Munich, Germany; German Centre for Infection Research, Munich, Germany.
Lancet Infect Dis. 2014 Dec;14(12):1196-207. doi: 10.1016/S1473-3099(14)70963-6. Epub 2014 Oct 30.
Modified vaccinia virus Ankara (MVA) is a promising viral vector platform for the development of an H5N1 influenza vaccine. Preclinical assessment of MVA-based H5N1 vaccines showed their immunogenicity and safety in different animal models. We aimed to assess the safety and immunogenicity of the MVA-haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals.
In a single-centre, double-blind phase 1/2a study, young volunteers (aged 18-28 years) were randomly assigned with a computer-generated list in equal numbers to one of eight groups and were given one injection or two injections intramuscularly at an interval of 4 weeks of a standard dose (10(8) plaque forming units [pfu]) or a ten times lower dose (10(7) pfu) of the MVA-H5-sfMR (vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus [H5N1 subtype]) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians who examined and administered the vaccine were masked to vaccine assignment. Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster immunisation 1 year after the first immunisation. Primary endpoint was safety. Secondary outcome was immunogenicity. The trial is registered with the Dutch Trial Register, number NTR3401.
79 of 80 individuals who were enrolled completed the study. No serious adverse events were identified. 11 individuals reported severe headache and lightheadedness, erythema nodosum, respiratory illness (accompanied by influenza-like symptoms), sore throat, or injection-site reaction. Most of the volunteers had one or more local (itch, pain, redness, and swelling) and systemic reactions (rise in body temperature, headache, myalgia, arthralgia, chills, malaise, and fatigue) after the first, second, and booster immunisations. Individuals who received the 10(7) dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 10(8) pfu induced significantly higher antibody responses after one and two immunisations than did 10(7) pfu when assessed with haemagglutination inhibition geometric mean titre at 8 weeks against H5N1 A/Vietnam/1194/2004 (30·2 [SD 3·8] vs 9·2 [2·3] and 108·1 [2·4] vs 15·8 [3·2]). 27 of 39 eligible individuals were enrolled in the booster immunisation study. A single shot of MVA-H5-sfMR 10(8) pfu prime immunisation resulted in higher antibody responses after the booster immunisation than did two shots of MVA-H5-sfMR at the ten times lower dose.
The MVA-based H5N1 vaccine was well tolerated and immunogenic and therefore the vaccine candidates arising from the MVA platform hold great promise for rapid development in response to a future influenza pandemic threat. However, the immunogenicity of this vaccine needs to be compared with conventional H5N1 inactivated non-adjuvanted vaccine candidates in head-to-head clinical trials.
European Research Council.
改良安卡拉痘苗病毒（MVA）是一种很有前途的病毒载体平台，可用于开发 H5N1 流感疫苗。基于 MVA 的 H5N1 疫苗的临床前评估表明，其在不同动物模型中具有免疫原性和安全性。我们旨在评估 MVA 血凝素基 H5N1 疫苗 MVA-H5-sfMR 在健康个体中的安全性和免疫原性。
在一项单中心、双盲 1/2a 期研究中，年轻志愿者（年龄 18-28 岁）按计算机生成的列表以相等数量随机分为 8 组，每组分别肌肉注射一次或两次标准剂量（10（8）蚀斑形成单位[pfu]）或十倍低剂量（10（7）pfu）的 MVA-H5-sfMR（编码流感 A/Vietnam/1194/2004 病毒[H5N1 亚型]血凝素基因的载体）或 MVA-F6-sfMR（空载体）疫苗。接受疫苗检查和接种的志愿者和医生对疫苗分配情况不知情。接受 MVA-H5-sfMR 疫苗接种的个体在首次免疫接种 1 年后有资格进行加强免疫接种。主要终点是安全性。次要结局是免疫原性。该试验在荷兰试验注册中心注册，编号为 NTR3401。
79 名入组的个体全部完成了研究。未发现严重不良事件。11 名个体报告了严重头痛和头晕、结节性红斑、呼吸道疾病（伴有流感样症状）、咽痛或注射部位反应。大多数志愿者在首次、第二次和加强免疫接种后均出现了一种或多种局部（瘙痒、疼痛、发红和肿胀）和全身反应（体温升高、头痛、肌痛、关节痛、寒战、不适和疲劳）。接受 10（7）剂量的个体全身反应较少。在 8 周时，用血凝抑制几何平均滴度评估，10（8）pfu 的 MVA-H5-sfMR 疫苗诱导的抗体应答在一次和两次免疫接种后均显著高于 10（7）pfu，对 H5N1 A/Vietnam/1194/2004 的抗体应答分别为 30.2（SD 3.8）与 9.2（2.3）和 108.1（2.4）与 15.8（3.2）。39 名符合条件的个体中有 27 名参加了加强免疫研究。单次 MVA-H5-sfMR 10（8）pfu 疫苗接种可导致加强免疫后产生更高的抗体应答，而两次接种 MVA-H5-sfMR 的低十倍剂量则不然。
基于 MVA 的 H5N1 疫苗具有良好的耐受性和免疫原性，因此基于 MVA 平台的候选疫苗在应对未来流感大流行威胁方面具有巨大的快速开发潜力。然而，这种疫苗的免疫原性需要在头对头临床试验中与传统的 H5N1 灭活非佐剂疫苗候选物进行比较。
欧洲研究理事会。
