Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
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18-59岁健康成人灭活SARS-CoV-2疫苗的安全性、耐受性和免疫原性：一项随机、双盲、安慰剂对照的1/2期临床试验
DOI：
10.1016/s1473-3099(20)30843-4
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Zhu F
中科院分区：
文献类型：
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作者：
Zhang Y;Zeng G;Pan H;Li C;Hu Y;Chu K;Han W;Chen Z;Tang R;Yin W;Chen X;Hu Y;Liu X;Jiang C;Li J;Yang M;Song Y;Wang X;Gao Q;Zhu F
由于与COVID-19大流行相关的发病率和死亡率前所未有，迫切需要一种针对COVID-19的疫苗。我们对冠状病毒候选灭活疫苗CoronaVac （Sinovac生命科学，北京，中国）进行了安全性、耐受性和免疫原性研究，该疫苗含有灭活的严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）。在这项随机、双盲、安慰剂对照的1/2期临床试验中，从中国江苏省睢宁县社区招募了年龄在18-59岁的健康成年人。排除有SARS-CoV-2暴露或感染史、腋窝温度高于37.0℃或对任何疫苗成分有过敏反应的成年人。一期试验的实验性疫苗采用细胞工厂工艺生产（CellSTACK细胞培养室10，康宁，吴江，中国），而二期试验的疫苗采用生物反应器工艺生产（ReadyToProcess WAVE 25， GE，瑞典于默奥）。1期试验以剂量递增的方式进行。在筛选时，参与者最初被（1:1）分开，没有特定的随机化，分为两个疫苗接种计划队列，第0和14天接种疫苗队列以及第0和28天接种疫苗队列，在每个队列中，前36名参与者被分配到第1区（低剂量CoronaVac[每剂量0.5 mL氢氧化铝稀释液3 μg），然后另外36名被分配到第2区（高剂量Coronavc[每剂量0.5 mL氢氧化铝稀释液6 μg]）。在每个分组中，参与者被随机分配（2:1），使用分组随机化，分组大小为6，分别服用两剂CoronaVac或两剂安慰剂。在2期试验中，在筛选时，参与者最初被分成（1:1），没有特定的随机化，分为第0天和第14天接种疫苗队列以及第0天和第28天接种疫苗队列，参与者被随机分配（2:2:1），使用块大小为5的块随机化，接受低剂量、高剂量CoronaVac或安慰剂两种剂量。参与者、调查人员和实验室工作人员对治疗分配不知情。主要安全终点是注射后28天内所有受试者至少服用一剂研究药物（安全人群）的不良反应。主要免疫原性结果是在0天和14天队列中最后一次剂量后第14天，以及在0天和28天队列中完成分配的两剂疫苗接种计划的参与者（按方案人群）的最后一次剂量后第28天，对活SARS-CoV-2的中和抗体的血清转化率。该试验已在ClinicalTrials.gov注册，编号NCT04352608，并已结束。在2020年4月16日至4月25日期间，144名参与者参加了第一阶段试验，在2020年5月3日至5月5日期间，600名参与者参加了第二阶段试验。743名参与者接受了至少一剂研究产品（n=143一期和n=600二期；安全人群）。在第一阶段试验中,不良反应的发生率为0和14天组七24的参与者(29%)的3 ug集团9(38%)的24 6μg组,和两个24日在安慰剂组(8%),和为0天、28天的群组三(13%)的24 3μg组,四个(17%)的24 6μg组,和三个23日在安慰剂组(13%)。3 μg组24名参与者中有11人（46%）、6 μg组24名参与者中有12人（50%）、安慰剂组24名参与者中没有人（0%）在接种0和14天疫苗后的第14天出现血清中和抗体转化；而在接种0天和28天后的第28天，3 μg组24人中有20人（83%）出现血清转化，6 μg组24人中有19人（79%）出现血清转化，安慰剂组24人中有1人（4%）出现血清转化。在第二阶段试验中,不良反应的发生率为0和14天组40(33%)的120名参与者3μg组,42(35%)的6μg组有120人,和13在安慰剂组(22%)的60,和为0天、28天的群组23岁(19%)的3μg组有120人,23(19%)的120 6μg组和安慰剂组的11(18%)的60。在第0天和第14天，118名参与者中，3 μg组有109名（92%）出现血清中和抗体转化，119名参与者中有117名（98%）出现血清中和抗体转化，60名安慰剂组中有2名（3%）出现血清中和抗体转化；而在第0天和第28天，3 μg组117人中有114人（97%）出现血清转化，6 μg组118人中有118人（100%）出现血清转化，安慰剂组59人中无血清转化（0%）。考虑到安全性、免疫原性和生产能力，3 μg剂量是未来三期试验疗效评估的建议剂量。国家重点研究发展计划和北京市科技计划。
With the unprecedented morbidity and mortality associated with the COVID-19 pandemic, a vaccine against COVID-19 is urgently needed. We investigated CoronaVac (Sinovac Life Sciences, Beijing, China), an inactivated vaccine candidate against COVID-19, containing inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for its safety, tolerability and immunogenicity. In this randomised, double-blind, placebo-controlled, phase 1/2 clinical trial, healthy adults aged 18–59 years were recruited from the community in Suining County of Jiangsu province, China. Adults with SARS-CoV-2 exposure or infection history, with axillary temperature above 37·0°C, or an allergic reaction to any vaccine component were excluded. The experimental vaccine for the phase 1 trial was manufactured using a cell factory process (CellSTACK Cell Culture Chamber 10, Corning, Wujiang, China), whereas those for the phase 2 trial were produced through a bioreactor process (ReadyToProcess WAVE 25, GE, Umea, Sweden). The phase 1 trial was done in a dose-escalating manner. At screening, participants were initially separated (1:1), with no specific randomisation, into two vaccination schedule cohorts, the days 0 and 14 vaccination cohort and the days 0 and 28 vaccination cohort, and within each cohort the first 36 participants were assigned to block 1 (low dose CoronaVac [3 μg per 0·5 mL of aluminium hydroxide diluent per dose) then another 36 were assigned to block 2 (high-dose Coronavc [6 μg per 0·5 mL of aluminium hydroxide diluent per dse]). Within each block, participants were randomly assigned (2:1), using block randomisation with a block size of six, to either two doses of CoronaVac or two doses of placebo. In the phase 2 trial, at screening, participants were initially separated (1:1), with no specific randomisation, into the days 0 and 14 vaccination cohort and the days 0 and 28 vaccination cohort, and participants were randomly assigned (2:2:1), using block randomisation with a block size of five, to receive two doses of either low-dose CoronaVac, high-dose CoronaVac, or placebo. Participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was adverse reactions within 28 days after injection in all participants who were given at least one dose of study drug (safety population). The primary immunogenic outcome was seroconversion rates of neutralising antibodies to live SARS-CoV-2 at day 14 after the last dose in the days 0 and 14 cohort, and at day 28 after the last dose in the days 0 and 28 cohort in participants who completed their allocated two-dose vaccination schedule (per-protocol population). This trial is registered with ClinicalTrials.gov, NCT04352608, and is closed to accrual. Between April 16 and April 25, 2020, 144 participants were enrolled in the phase 1 trial, and between May 3 and May 5, 2020, 600 participants were enrolled in the phase 2 trial. 743 participants received at least one dose of investigational product (n=143 for phase 1 and n=600 for phase 2; safety population). In the phase 1 trial, the incidence of adverse reactions for the days 0 and 14 cohort was seven (29%) of 24 participants in the 3 ug group, nine (38%) of 24 in the 6 μg group, and two (8%) of 24 in the placebo group, and for the days 0 and 28 cohort was three (13%) of 24 in the 3 μg group, four (17%) of 24 in the 6 μg group, and three (13%) of 23 in the placebo group. The seroconversion of neutralising antibodies on day 14 after the days 0 and 14 vaccination schedule was seen in 11 (46%) of 24 participants in the 3 μg group, 12 (50%) of 24 in the 6 μg group, and none (0%) of 24 in the placebo group; whereas at day 28 after the days 0 and 28 vaccination schedule, seroconversion was seen in 20 (83%) of 24 in the 3 μg group, 19 (79%) of 24 in the 6 μg group, and one (4%) of 24 in the placebo group. In the phase 2 trial, the incidence of adverse reactions for the days 0 and 14 cohort was 40 (33%) of 120 participants in the 3 μg group, 42 (35%) of 120 in the 6 μg group, and 13 (22%) of 60 in the placebo group, and for the days 0 and 28 cohort was 23 (19%) of 120 in the 3 μg group, 23 (19%) of 120 in the 6 μg group, and 11 (18%) of 60 for the placebo group. Seroconversion of neutralising antibodies was seen for 109 (92%) of 118 participants in the 3 μg group, 117 (98%) of 119 in the 6 μg group, and two (3%) of 60 in the placebo group at day 14 after the days 0 and 14 schedule; whereas at day 28 after the days 0 and 28 schedule, seroconversion was seen in 114 (97%) of 117 in the 3 μg group, 118 (100%) of 118 in the 6 μg group, and none (0%) of 59 in the placebo group. Taking safety, immunogenicity, and production capacity into account, the 3 μg dose of CoronaVac is the suggested dose for efficacy assessment in future phase 3 trials. Chinese National Key Research and Development Program and Beijing Science and Technology Program.