Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial.
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DOI：
10.1016/s1473-3099(21)00319-4
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发表时间：
2021-12
期刊：
影响因子：
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通讯作者：
Gao Q
中科院分区：
文献类型：
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作者：
Han B;Song Y;Li C;Yang W;Ma Q;Jiang Z;Li M;Lian X;Jiao W;Wang L;Shu Q;Wu Z;Zhao Y;Li Q;Gao Q
针对儿童和青少年的SARS-CoV-2疫苗将在遏制COVID-19大流行方面发挥重要作用。在这里，我们的目的是评估候选COVID-19疫苗CoronaVac（含有灭活SARS-CoV-2）在3-17岁儿童和青少年中的安全性、耐受性和免疫原性。我们在赞皇（中国河北）河北省疾病预防控制中心对3-17岁的健康儿童和青少年进行了CoronaVac的双盲、随机、对照、I/II期临床试验。排除了有SARS-CoV-2暴露或感染史的个人。通过肌内注射以两个剂量（第0天和第28天）给予疫苗（在0·5 mL氢氧化铝佐剂中）或仅氢氧化铝（仅明矾，对照）。我们在72名参与者中进行了1期试验，其中三组年龄递减，两组剂量递增（每次注射1.5 μg或3.0 μg）。在每个区组内，通过区组随机化将参与者随机分配（3：1），仅接受CoronaVac或明矾。在第2阶段，通过区组随机化将参与者随机分配（2：2：1）接受CoronaVac，剂量为1.5 μg或3.0 μg/剂，或仅接受明矾。所有参与者、研究者和实验室工作人员均对分组设盲。主要安全性终点是所有接受至少一剂的参与者每次注射后28天内的不良反应。在符合方案人群中评估的主要免疫原性终点是第二次注射后28天中和抗体对活SARS-CoV-2的血清转化率。本研究正在进行中，并在ClinicalTrials.gov注册，NCT 04551547。在2020年10月31日至2020年12月2日期间，72名受试者入组第1阶段，在2020年12月12日至2020年12月30日期间，480名受试者入组第2阶段。550名受试者仅接受了至少一剂疫苗或明矾（1期n=71，2期n=479;安全性人群）。在I期和II期的合并安全性特征中，注射后28天内，1.5 μg组219名参与者中有56名（26%）发生任何不良反应，3.0 μg组217名参与者中有63名（29%），仅明矾组114名参与者中有27名（24%），无显著差异（p= 0.55）。大多数不良反应的严重程度为轻度和中度。注射部位疼痛是最常报告的事件（550名参与者中有73名[13%]），1.5 μg组219名参与者中有36名（16%），3.0 μg组217名参与者中有35名（16%），仅明矾组有2名（2%）。截至2021年6月12日，仅明矾组报告了1起肺炎严重不良事件，被认为与疫苗接种无关。在第1阶段，在27/27名参与者中观察到第二次给药后中和抗体的血清转化（100.0%[95% CI 87.2 - 100.0]），26/26例受试者（100·0% [86·8-100·0]），几何平均滴度为55·0（95% CI 38·9-77·9）和117·4（87·8-157·0）。在第2阶段，186名参与者中有180人出现血清转化（96.8%[93.1 - 98.8]），180/180名参与者（100·0% [98·0-100·0]），几何平均滴度为86·4（73·9-101·0）和142·2（124·7-162·1）。在仅明矾组中没有可检测到的抗体应答。CoronaVac在3-17岁的儿童和青少年中耐受性良好且安全，并诱导体液反应。3.0 μg剂量诱导的中和抗体滴度高于1.5 μg剂量。结果支持在儿童和青少年中使用3·0 μg剂量和两次免疫接种计划进行进一步研究。国家重点研究发展计划和北京市科技计划。
A vaccine against SARS-CoV-2 for children and adolescents will play an important role in curbing the COVID-19 pandemic. Here we aimed to assess the safety, tolerability, and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in children and adolescents aged 3–17 years. We did a double-blind, randomised, controlled, phase 1/2 clinical trial of CoronaVac in healthy children and adolescents aged 3–17 years old at Hebei Provincial Center for Disease Control and Prevention in Zanhuang (Hebei, China). Individuals with SARS-CoV-2 exposure or infection history were excluded. Vaccine (in 0·5 mL aluminum hydroxide adjuvant) or aluminum hydroxide only (alum only, control) was given by intramuscular injection in two doses (day 0 and day 28). We did a phase 1 trial in 72 participants with an age de-escalation in three groups and dose-escalation in two blocks (1·5 μg or 3·0 μg per injection). Within each block, participants were randomly assigned (3:1) by means of block randomisation to receive CoronaVac or alum only. In phase 2, participants were randomly assigned (2:2:1) by means of block randomisation to receive either CoronaVac at 1·5 μg or 3·0 μg per dose, or alum only. All participants, investigators, and laboratory staff were masked to group allocation. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint assessed in the per-protocol population was seroconversion rate of neutralising antibody to live SARS-CoV-2 at 28 days after the second injection. This study is ongoing and is registered with ClinicalTrials.gov, NCT04551547. Between Oct 31, 2020, and Dec 2, 2020, 72 participants were enrolled in phase 1, and between Dec 12, 2020, and Dec 30, 2020, 480 participants were enrolled in phase 2. 550 participants received at least one dose of vaccine or alum only (n=71 for phase 1 and n=479 for phase 2; safety population). In the combined safety profile of phase 1 and phase 2, any adverse reactions within 28 days after injection occurred in 56 (26%) of 219 participants in the 1·5 μg group, 63 (29%) of 217 in the 3·0 μg group, and 27 (24%) of 114 in the alum-only group, without significant difference (p=0·55). Most adverse reactions were mild and moderate in severity. Injection site pain was the most frequently reported event (73 [13%] of 550 participants), occurring in 36 (16%) of 219 participants in the 1·5 μg group, 35 (16%) of 217 in the 3·0 μg group, and two (2%) in the alum-only group. As of June 12, 2021, only one serious adverse event of pneumonia has been reported in the alum-only group, which was considered unrelated to vaccination. In phase 1, seroconversion of neutralising antibody after the second dose was observed in 27 of 27 participants (100·0% [95% CI 87·2–100·0]) in the 1·5 μg group and 26 of 26 participants (100·0% [86·8-100·0]) in the 3·0 μg group, with the geometric mean titres of 55·0 (95% CI 38·9–77·9) and 117·4 (87·8–157·0). In phase 2, seroconversion was seen in 180 of 186 participants (96·8% [93·1–98·8]) in the 1·5 μg group and 180 of 180 participants (100·0% [98·0–100·0]) in the 3·0 μg group, with the geometric mean titres of 86·4 (73·9–101·0) and 142·2 (124·7–162·1). There were no detectable antibody responses in the alum-only groups. CoronaVac was well tolerated and safe and induced humoral responses in children and adolescents aged 3–17 years. Neutralising antibody titres induced by the 3·0 μg dose were higher than those of the 1·5 μg dose. The results support the use of 3·0 μg dose with a two-immunisation schedule for further studies in children and adolescents. The Chinese National Key Research and Development Program and the Beijing Science and Technology Program.