Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.
Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.
复制标题
灭活的SARS-COV-2疫苗的安全性和免疫原性，BBIBP-CORV：随机，双盲，安慰剂对照，1/2期试验。
DOI：
10.1016/s1473-3099(20)30831-8
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Xia S;Zhang Y;Wang Y;Wang H;Yang Y;Gao GF;Tan W;Wu G;Xu M;Lou Z;Huang W;Xu W;Huang B;Wang H;Wang W;Zhang W;Li N;Xie Z;Ding L;You W;Zhao Y;Yang X;Liu Y;Wang Q;Huang L;Yang Y;Xu G;Luo B;Wang W;Liu P;Guo W;Yang X
正在进行的新冠肺炎大流行需要加快测试候选疫苗的努力。我们的目的是评估SARS-CoV-2灭活疫苗候选疫苗BBIBP-COV在人类中的安全性和免疫原性。我们在河南省商丘市梁园区疾病预防控制中心进行了一项随机、双盲、安慰剂对照的1/2期试验，中国。在第一阶段中，18-80岁的健康人群被分成两个年龄组(18-59岁和≥60岁)，分别在0天和28天接种疫苗或安慰剂，两剂剂量分别为2μg、4μg或8μg。在第二阶段，健康成人(18-59岁)被随机分配(1：1：1：1)接种疫苗或安慰剂，单剂方案为0天8μg，双剂方案为0天和14天，0和21天，或0和28天4μg。每个队列中的参与者通过分层区组随机(区组大小为8)随机分配，并被分配(3：1)接受疫苗或安慰剂。小组分配对参与者、调查人员和结果评估人员隐瞒。主要结果是安全性和耐受性。次要结果是免疫原性，评估为对传染性SARS-CoV-2的中和抗体反应。这项研究注册在www.chictr.org.cn，ChiCTR2000032459。在第一阶段，192名参与者(平均年龄53·7岁[SD 15·6])被随机分配到接种疫苗(2μg[n=24]、4μg[n=24]或8μg[n=24]两个年龄组[18-59岁和≥60岁])或安慰剂(n=24)。在144名疫苗接受者中，有42人(29%)在接种后的头7天内报告了至少一种不良反应。最常见的全身不良反应是发热(18~59岁，2μg组1例[4%]，4μg组1例[4%]，8μg组2例[8%]；≥60岁，8μg组1例[4%])。所有不良反应的严重程度均为轻度或中度。接种后28天内未报告严重不良事件。中和抗体几何平均滴度在18~59岁组(87·7[95%CI·9~118·6]，2μg组；2 11·2[15 8·9~2 80·6]，4μg组；2 2 8·7[186·1~2 81·1]，8μg组)和60岁及以上组(80·7[65·4~99·6]，2μg组；13 1·5[10 8·2~15 9·7]，4μg组；和170.87[133.0-219.5]，8μg组)与安慰剂组(2.0[2.0-2.0])比较。在第二阶段，448名参与者(平均年龄41·7岁[SD 9·9])被随机分配到接种疫苗(0天8μg[n=84]或0和14天4μg[n=84]、0和21天[n=84]或0和28天[n=84])或安慰剂。在336例疫苗接受者中，76例(23%)在前7天内至少出现一次不良反应，其中33例(39%)，8μg第0天；18例(21%)，4μg第0天和14天；15例[18%]，4μg第0天和21天；10例[12%]，4μg第0天和28天。在4μg 0和21天组中，1名安慰剂接受者报告3级发烧，但自我限制并痊愈。所有其他不良反应的严重程度均为轻度或中度。最常见的全身不良反应是发热(1例[1%]，8μg第0天；1例[1%]，4μg第0天和14天；3例[4%]，4μg第0天和21天；2例[2%]，4μg第0天和28天)。疫苗中和抗体滴度在第4μg第0天和第14天(169.5，95%CI 132.217.1)，第0和第21天(282.7,221.22-361.4)，第0和第28天(218.0,181.8261·3)显著高于第8μg第0天(14.7，11.6-18.8；均P<；0·001)。SARS-CoV-2灭活疫苗BBIBP-COV在两个年龄组的所有测试剂量下都是安全和耐受性良好的。接种后第42天，所有疫苗接种者均诱导产生针对SARS-CoV-2的体液免疫应答。在第0天和第21天或第0天和第28天用4μg疫苗进行两剂免疫，中和抗体效价均高于单剂8μg疫苗或4μg疫苗在0天和14天的中和效价。国家中国重点研究计划项目、中国重大传染病重大计划、中国新药创制国家重大计划、北京市科技计划。
The ongoing COVID-19 pandemic warrants accelerated efforts to test vaccine candidates. We aimed to assess the safety and immunogenicity of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate, BBIBP-CorV, in humans. We did a randomised, double-blind, placebo-controlled, phase 1/2 trial at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan Province, China. In phase 1, healthy people aged 18–80 years, who were negative for serum-specific IgM/IgG antibodies against SARS-CoV-2 at the time of screening, were separated into two age groups (18–59 years and ≥60 years) and randomly assigned to receive vaccine or placebo in a two-dose schedule of 2 μg, 4 μg, or 8 μg on days 0 and 28. In phase 2, healthy adults (aged 18–59 years) were randomly assigned (1:1:1:1) to receive vaccine or placebo on a single-dose schedule of 8 μg on day 0 or on a two-dose schedule of 4 μg on days 0 and 14, 0 and 21, or 0 and 28. Participants within each cohort were randomly assigned by stratified block randomisation (block size eight) and allocated (3:1) to receive vaccine or placebo. Group allocation was concealed from participants, investigators, and outcome assessors. The primary outcomes were safety and tolerability. The secondary outcome was immunogenicity, assessed as the neutralising antibody responses against infectious SARS-CoV-2. This study is registered with www.chictr.org.cn, ChiCTR2000032459. In phase 1, 192 participants were enrolled (mean age 53·7 years [SD 15·6]) and were randomly assigned to receive vaccine (2 μg [n=24], 4 μg [n=24], or 8 μg [n=24] for both age groups [18–59 years and ≥60 years]) or placebo (n=24). At least one adverse reaction was reported within the first 7 days of inoculation in 42 (29%) of 144 vaccine recipients. The most common systematic adverse reaction was fever (18–59 years, one [4%] in the 2 μg group, one [4%] in the 4 μg group, and two [8%] in the 8 μg group; ≥60 years, one [4%] in the 8 μg group). All adverse reactions were mild or moderate in severity. No serious adverse event was reported within 28 days post vaccination. Neutralising antibody geometric mean titres were higher at day 42 in the group aged 18–59 years (87·7 [95% CI 64·9–118·6], 2 μg group; 211·2 [158·9–280·6], 4 μg group; and 228·7 [186·1–281·1], 8 μg group) and the group aged 60 years and older (80·7 [65·4–99·6], 2 μg group; 131·5 [108·2–159·7], 4 μg group; and 170·87 [133·0–219·5], 8 μg group) compared with the placebo group (2·0 [2·0–2·0]). In phase 2, 448 participants were enrolled (mean age 41·7 years [SD 9·9]) and were randomly assigned to receive the vaccine (8 μg on day 0 [n=84] or 4 μg on days 0 and 14 [n=84], days 0 and 21 [n=84], or days 0 and 28 [n=84]) or placebo on the same schedules (n=112). At least one adverse reaction within the first 7 days was reported in 76 (23%) of 336 vaccine recipients (33 [39%], 8 μg day 0; 18 [21%], 4 μg days 0 and 14; 15 [18%], 4 μg days 0 and 21; and ten [12%], 4 μg days 0 and 28). One placebo recipient in the 4 μg days 0 and 21 group reported grade 3 fever, but was self-limited and recovered. All other adverse reactions were mild or moderate in severity. The most common systematic adverse reaction was fever (one [1%], 8 μg day 0; one [1%], 4 μg days 0 and 14; three [4%], 4 μg days 0 and 21; two [2%], 4 μg days 0 and 28). The vaccine-elicited neutralising antibody titres on day 28 were significantly greater in the 4 μg days 0 and 14 (169·5, 95% CI 132·2–217·1), days 0 and 21 (282·7, 221·2–361·4), and days 0 and 28 (218·0, 181·8–261·3) schedules than the 8 μg day 0 schedule (14·7, 11·6–18·8; all p<0·001). The inactivated SARS-CoV-2 vaccine, BBIBP-CorV, is safe and well tolerated at all tested doses in two age groups. Humoral responses against SARS-CoV-2 were induced in all vaccine recipients on day 42. Two-dose immunisation with 4 μg vaccine on days 0 and 21 or days 0 and 28 achieved higher neutralising antibody titres than the single 8 μg dose or 4 μg dose on days 0 and 14. National Program on Key Research Project of China, National Mega projects of China for Major Infectious Diseases, National Mega Projects of China for New Drug Creation, and Beijing Science and Technology Plan.