Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial

BackgroundModified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts.MethodsThe trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637.ResultsBetween March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment.ConclusionsThe neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA.Trial registrationClinicalTrials.gov NCT01144637背景：改良痘苗安卡拉病毒（Modified Vaccinia Ankara, MVA）是一种处于晚期研发阶段的非复制型天花活病毒疫苗。本研究开展一项随机、双盲、安慰剂对照的Ⅲ期临床试验，旨在验证连续三批生产的MVA的体液免疫原性等效性，并以心脏监测指标为重点验证MVA的安全性与耐受性。 方法：本试验在美国34家研究中心开展。招募18~40岁未接种过痘苗病毒的健康成年人，按照1:1:1:1的随机分配方案将其随机分为4组。第1~3组受试者接受两剂来自上述连续三批MVA的接种，第4组受试者接受两剂安慰剂接种，两次接种间隔4周。除负责疫苗配制与接种的工作人员外，所有受试者与研究人员均对分组分配设盲。整个试验过程中，安全性评估以心脏监测为核心内容。采用空斑减少中和试验（Plaque Reduction Neutralization Test, PRNT）与酶联免疫吸附试验（Enzyme-Linked Immunosorbent Assay, ELISA）检测痘苗病毒特异性抗体滴度。本次试验的主要免疫原性终点为第4次随访时，通过PRNT检测的两剂MVA接种后的几何平均滴度（Geometric Mean Titers, GMT）。本试验已在ClinicalTrials.gov注册，注册号为NCT01144637。 结果：2013年3月至2014年5月期间，共纳入4005名受试者，其中3003名接受至少一剂MVA接种，1002名接受安慰剂接种。三批MVA在第二剂接种后两周诱导产生的抗体滴度等效，PRNT与ELISA检测的血清阳转率分别为99.8%与99.7%。总体而言，MVA接种组中有180名（6.0%）受试者报告至少1起与试验相关的非主动上报不良事件（Adverse Event, AE），安慰剂组为29名（2.9%）。接种耐受性良好，未出现显著的安全性问题，尤其是心脏相关评估指标无异常。 结论：三批MVA各自诱导产生的中和抗体与总抗体滴度均等效。本试验的健康受试者群体未出现显著的安全性问题，尤其是心脏安全性方面，由此证实MVA具有优异的安全性与耐受性。 试验注册：ClinicalTrials.gov NCT01144637