Safety and immunogenicity of S-Trimer (SCB-2019), a protein subunit vaccine candidate for COVID-19 in healthy adults: a phase 1, randomised, double-blind, placebo-controlled trial.
Safety and immunogenicity of S-Trimer (SCB-2019), a protein subunit vaccine candidate for COVID-19 in healthy adults: a phase 1, randomised, double-blind, placebo-controlled trial.
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DOI：
10.1016/s0140-6736(21)00241-5
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发表时间：
2021-02-20
期刊：
影响因子：
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通讯作者：
Clemens R
中科院分区：
文献类型：
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作者：
Richmond P;Hatchuel L;Dong M;Ma B;Hu B;Smolenov I;Li P;Liang P;Han HH;Liang J;Clemens R
作为加速开发针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 疫苗的一部分，我们报告了 SCB-2019 的剂量探索和佐剂合理性研究，SCB-2019 是一种候选蛋白亚单位疫苗，含有稳定的三聚体形式的刺突 (S)-蛋白 (S-Trimer) 和两种不同的佐剂。我们的研究是在澳大利亚一家专业临床试验中心进行的一期随机双盲安慰剂对照试验。我们招募了两个年龄组的健康成年志愿者：年轻人（18-54 岁）和老年人（55-75 岁）。根据研究资助者准备的清单，参与者被随机分配疫苗或安慰剂。参与者将接受两剂 SCB-2019（3 μg、9 μg 或 30 μg）或安慰剂（0·9% NaCl），间隔 21 天。 SCB-2019 要么没有佐剂（仅 S-三聚体蛋白），要么用 AS03 或 CpG/Alum 佐剂。分配的治疗是在不透明注射器中进行的，以维持分配的掩蔽。每次接种疫苗后评估反应原性 7 天。通过 ELISA 测量 SCB-2019 结合 IgG 抗体和 ACE2 竞争性阻断 IgG 抗体，并通过野生型 SARS-CoV-2 微中和测定测量中和抗体。通过流式细胞仪细胞内细胞因子染色测量细胞对合并的 S 蛋白肽的反应。该试验已在 ClinicalTrials.gov 注册，NCT04405908；这是一项临时分析，研究仍在继续。 2020年6月19日至9月23日期间，共有151名志愿者报名；三人退出，其中两人出于个人原因，一人因不相关的严重不良事件（垂体腺瘤）而退出。 148 名参与者在第二次给药后进行了至少 4 周的随访，并被纳入本次分析（数据库锁定，2020 年 10 月 23 日）。疫苗接种耐受性良好，有两起 3 级不良事件（9 μg AS03 佐剂组和 9 μg CpG/Alum 佐剂组出现疼痛）。大多数局部不良事件是轻微的注射部位疼痛，含有 AS03 佐剂的 SCB-2019 制剂（44-69%）的局部事件比含有 CpG/Alum 佐剂（6-44%）或不含佐剂（3-13%）的 SCB-2019 制剂更常见。第一次给药后，年轻人（38%）的全身不良事件比老年人（17%）更常见，但第二次给药后两个年龄组的全身不良事件均增加到相似水平（老年人为 30%，年轻人为 34%）。不含佐剂的 SCB-2019 引发了最小的免疫反应（第 50 天时发生了 3 次血清转化），但含有固定剂量 AS03 或 CpG/Alum 佐剂的 SCB-2019 在年轻人和老年人中均诱导了结合和中和抗体的高滴度和血清转化率（第 36 天时抗 SCB-2019 IgG 抗体几何平均滴度为AS03 为 1567–4452，CpG/Alum 为 174–2440）。所有 AS03 剂量组和 CpG/Alum 30 μg 组的滴度均高于一组 COVID-19 患者恢复期血清样本中记录的滴度。两种佐剂 SCB-2019 制剂均引发 T 辅助细胞 1 偏向的 CD4+ T 细胞反应。 SCB-2019 疫苗包含与 AS03 或 CpG/Alum 佐剂配制而成的 S-三聚体蛋白，可引发针对 SARS-CoV-2 的强大体液和细胞免疫反应，并具有高病毒中和活性。两种佐剂疫苗制剂均具有良好的耐受性，适合进一步的临床开发。三叶草生物制药公司和流行病防范创新联盟。
As part of the accelerated development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we report a dose-finding and adjuvant justification study of SCB-2019, a protein subunit vaccine candidate containing a stabilised trimeric form of the spike (S)-protein (S-Trimer) combined with two different adjuvants. Our study is a phase 1, randomised, double-blind placebo-controlled trial at a specialised clinical trials centre in Australia. We enrolled healthy adult volunteers in two age groups: younger adults (aged 18–54 years) and older adults (aged 55–75 years). Participants were randomly allocated either vaccine or placebo using a list prepared by the study funder. Participants were to receive two doses of SCB-2019 (either 3 μg, 9 μg, or 30 μg) or a placebo (0·9% NaCl) 21 days apart. SCB-2019 either had no adjuvant (S-Trimer protein alone) or was adjuvanted with AS03 or CpG/Alum. The assigned treatment was administered in opaque syringes to maintain masking of assignments. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding IgG antibodies and ACE2-competitive blocking IgG antibodies by ELISA and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay. Cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining. This trial is registered with ClinicalTrials.gov, NCT04405908; this is an interim analysis and the study is continuing. Between June 19 and Sept 23, 2020, 151 volunteers were enrolled; three people withdrew, two for personal reasons and one with an unrelated serious adverse event (pituitary adenoma). 148 participants had at least 4 weeks of follow-up after dose two and were included in this analysis (database lock, Oct 23, 2020). Vaccination was well tolerated, with two grade 3 solicited adverse events (pain in 9 μg AS03-adjuvanted and 9 μg CpG/Alum-adjuvanted groups). Most local adverse events were mild injection-site pain, and local events were more frequent with SCB-2019 formulations containing AS03 adjuvant (44–69%) than with those containing CpG/Alum adjuvant (6–44%) or no adjuvant (3–13%). Systemic adverse events were more frequent in younger adults (38%) than in older adults (17%) after the first dose but increased to similar levels in both age groups after the second dose (30% in older and 34% in younger adults). SCB-2019 with no adjuvant elicited minimal immune responses (three seroconversions by day 50), but SCB-2019 with fixed doses of either AS03 or CpG/Alum adjuvants induced high titres and seroconversion rates of binding and neutralising antibodies in both younger and older adults (anti-SCB-2019 IgG antibody geometric mean titres at day 36 were 1567–4452 with AS03 and 174–2440 with CpG/Alum). Titres in all AS03 dose groups and the CpG/Alum 30 μg group were higher than were those recorded in a panel of convalescent serum samples from patients with COVID-19. Both adjuvanted SCB-2019 formulations elicited T-helper-1-biased CD4+ T-cell responses. The SCB-2019 vaccine, comprising S-Trimer protein formulated with either AS03 or CpG/Alum adjuvants, elicited robust humoral and cellular immune responses against SARS-CoV-2, with high viral neutralising activity. Both adjuvanted vaccine formulations were well tolerated and are suitable for further clinical development. Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.