Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
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DOI：
10.1016/s0140-6736(20)31605-6
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发表时间：
2020-08-15
期刊：
影响因子：
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通讯作者：
Chen W
中科院分区：
文献类型：
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作者：
Zhu FC;Guan XH;Li YH;Huang JY;Jiang T;Hou LH;Li JX;Yang BF;Wang L;Wang WJ;Wu SP;Wang Z;Wu XH;Xu JJ;Zhang Z;Jia SY;Wang BS;Hu Y;Liu JJ;Zhang J;Qian XA;Li Q;Pan HX;Jiang HD;Deng P;Gou JB;Wang XW;Wang XH;Chen W
这是第一项评估候选非复制型5型腺病毒（Ad 5）载体COVID-19疫苗免疫原性和安全性的随机对照试验，旨在确定候选疫苗的适当剂量以进行有效性研究。这项随机、双盲、安慰剂对照、2期的Ad 5载体COVID-19疫苗试验是在中国武汉的一个中心进行的。年龄在18岁或以上的健康成年人，HIV阴性且既往无严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染，有资格参与并随机分配接受1 × 1011病毒颗粒/mL或5 × 1010病毒颗粒/mL剂量的疫苗或安慰剂。 研究者以2：1：1的比例将受试者分配到接受单次肌肉注射的手臂中。随机化列表（区组大小4）由独立的统计学家生成。参与者、研究者和进行实验室分析的工作人员对组分配不知情。免疫原性的主要终点是第28天对受体结合结构域（RBD）的特异性ELISA抗体应答和中和抗体应答的几何平均滴度（GMT）。安全性评价的主要终点是14天内不良反应的发生率。所有招募的至少接受一次给药的受试者均纳入主要和安全性分析。本研究注册于ClinicalTrials.gov，NCT 04341389。在2020年4月11日至16日期间招募了603名志愿者并进行了资格筛选。508名合格受试者（50%男性;平均年龄39.7岁，SD 12.5）同意参加试验，并随机分配接受疫苗（1 × 1011病毒颗粒n=253; 5 × 1010病毒颗粒n=129）或安慰剂（n=126）。 在1 × 1011和5 × 1010个病毒颗粒剂量组中，第28天RBD特异性ELISA抗体峰值分别为656·5（95% CI 575·2-749·2）和571·0（467·6-697·3），血清转换率分别为96%（95% CI 93-98）和97%（92-99）。 两种剂量的疫苗均诱导了对SARS-CoV-2活病毒的显著中和抗体应答，在接受1 × 1011和5 × 1010病毒颗粒的参与者中，GMT分别为19.5（95% CI 16.8 - 22.7）和18.3（14.4 - 23.3）。 在1 × 1011和5 × 1010病毒颗粒剂量组中，分别在253例受试者中的227例（90%，95% CI 85-93）和129例受试者中的113例（88%，81-92）中观察到疫苗接种后特异性干扰素γ酶联免疫斑点试验应答。 在1 × 1011和5 × 1010病毒颗粒剂量组中，分别有183/253（72%）和96/129（74%）例受试者报告了征集性不良反应。 1 × 1011病毒颗粒剂量组中有24名（9%）参与者报告了严重不良反应，5 × 1010病毒颗粒剂量组中有1名（1%）参与者报告了严重不良反应。 未记录严重不良反应。5 × 1010病毒颗粒的Ad 5载体COVID-19疫苗是安全的，并且在单次免疫后在大多数接受者中诱导了显著的免疫应答。 国家重点研发计划、国家科技重大专项、康赛诺生物制品。
This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study. This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389. 603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented. The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation. National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.