Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in healthy adults: an observer-blind, randomised, phase 1 trial
Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in healthy adults: an observer-blind, randomised, phase 1 trial
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DOI：
10.1016/s1473-3099(20)30733-7
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发表时间：
2021-08-24
影响因子：
56.3
通讯作者：
Borkowski, Astrid
中科院分区：
文献类型：
--
作者：
Han, Htay-Htay;Diaz, Clemente;Borkowski, Astrid
摘要 背景 寨卡病毒是一种由埃及伊蚊和白纹伊蚊传播的黄病毒，与先天畸形和神经并发症病例有关。由于缺乏特异性治疗，预防性寨卡病毒疫苗成为未满足的医疗需求。我们评估了三种剂量的纯化、灭活寨卡病毒候选疫苗在未接触过黄病毒和已接触过黄病毒的健康成人中的安全性和免疫原性。方法 这项由两部分组成、多中心、观察者盲法、随机、安慰剂对照的 1 期试验在美国的 7 个医疗诊所和波多黎各的 2 个医疗诊所进行。符合资格的参与者是 18-49 岁的健康成年人。使用申办者提供的随机方案，将参与者随机分配 (1:1:1:1) 到四组，接受两次肌肉注射盐水安慰剂或含有 2 μg、5 μg 或 10 μg 抗原的 TAK-426，间隔 28 天。参与者、研究人员和疫苗管理人员不知道分组情况。该研究的第一部分评估了未接触过黄病毒的参与者，第二部分评估了接受过黄病毒的参与者。主要结局是安全性、耐受性和免疫原性，基于每次给药后 7 天内引起的局部反应和全身不良事件；每次给药后 28 天内未经请求的不良事件和严重不良事件；以及第二次给药后 28 天中和抗寨卡病毒抗体的几何平均滴度 (GMT)。对所有至少接受一剂疫苗的参与者进行了安全评估。免疫原性评估是在符合方案的一组中进行的，包括所有接受至少一剂疫苗并在基线和至少一个疫苗接种后时间点提供有效血清学结果的参与者，没有重大方案违规。该试验正在进行中，并在 ClinicalTrials.gov 上注册（NCT03343626）。研究结果 2017年11月13日至2018年10月24日期间，对894名志愿者进行了筛查，并招募了271名志愿者（125名未接受过黄病毒的参与者和146名接受过黄病毒的参与者）。所有 TAK-426 剂量均具有良好的耐受性，没有死亡，没有与疫苗相关的严重不良事件，并且主要为轻度至中度不良事件的发生率相似。 TAK-426 在未接触黄病毒和黄病毒引发的参与者中均引起抗体 GMT 的剂量依赖性增加。第 2 剂给药后 28 天，未接触过黄病毒的受试者中，2 μg TAK-426 组的空斑减少中和测试 GMT 为 1130 (95% CI 749-1703)，5 μg TAK-426 组为 1992 (1401-2833)，10 μg TAK-426 组为 3690 (2677-5086)。 TAK-426组。在成对比较中，10 μg 组接种两次疫苗后的反应显着高于 2 μg 组（GMT 比率 3 中心点 27 [95% CI 1 中心点 98-5 中心点 39]，p
Summary Background Zika virus, a flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes, is associated with cases of congenital malformations and neurological complications. Absence of specific treatment makes a prophylactic Zika virus vaccine an unmet medical need. We assessed safety and immunogenicity of three doses of a purified, inactivated, Zika virus vaccine candidate in healthy flavivirus-naive and flavivirus-primed adults. Methods This two-part, multicentre, observer-blind, randomised, placebo-controlled, phase 1 trial was done at seven medical clinics in the USA and two in Puerto Rico. Eligible participants were healthy adults aged 18-49 years. Participants were randomly assigned (1:1:1:1), using a sponsor-supplied randomisation scheme, to four groups to receive two intramuscular injections, 28 days apart, of saline placebo or TAK-426 containing 2 mu g, 5 mu g, or 10 mu g antigen. Participants, investigators, and vaccine administrating personnel were masked to group assignment. Part 1 of the study assessed flavivirus-naive participants and part 2 assessed flavivirus-primed participants. The primary outcomes were safety, tolerability, and immunogenicity based on solicited local reactions and solicited systemic adverse events in the 7 days after each dose; unsolicited adverse events and serious adverse events in the 28 days after each dose; and geometric mean titres (GMTs) of neutralising anti-Zika virus antibodies at 28 days after the second dose. Safety assessments were done in all participants who received at least one dose of vaccine. Immunogenicity assessments were in the per-protocol set, comprising all participants who received at least one dose of vaccine and provided valid serology results at baseline and at least one post-vaccination timepoint, with no major protocol violations. The trial is ongoing and is registered at ClinicalTrials.gov (NCT03343626). Findings Between Nov 13, 2017, and Oct 24, 2018, 894 volunteers were screened and 271 enrolled (125 flavivirus-naive and 146 flavivirus-primed participants). All TAK-426 doses were well tolerated with no deaths, no vaccine-related serious adverse events, and similar rates of mainly mild to moderate adverse events. TAK-426 elicited dose-dependent increases in antibody GMTs in both flavivirus-naive and flavivirus-primed participants. 28 days after dose 2, plaque-reduction neutralisation test GMTs in flavivirus-naive participants were 1130 (95% CI 749-1703) in the 2 mu g TAK-426 group, 1992 (1401-2833) in the 5 mu g TAK-426 group, and 3690 (2677-5086) in the 10 mu g TAK-426 group. In pairwise comparisons, responses after two vaccinations in the 10 mu g group were significantly greater than in the 2 mu g group (GMT ratio 3 center dot 27 [95% CI 1 center dot 98-5 center dot 39], p