NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
Lancet Infect Dis. 2022 Aug;22(8):1131-1141. doi: 10.1016/S1473-3099(22)00271-7. Epub 2022 May 9.
Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.
The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.
Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6-77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3-214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030-27 162), which increased to 37 460 ELU/mL (31 996-43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41-1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996-30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826-64 452), with a geometric mean fold change of 2·19 (1·90-2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37-14·32) and 15·90 (12·92-19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24-16·54] in the BNT162b2 group and 6·22 [3·90-9·92] in the mRNA-1273 group).
Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose.
UK Vaccine Task Force and National Institute for Health Research.
一些高收入国家已部署了第四剂 COVID-19 疫苗，但第四剂的临床需求、有效性、时间和剂量仍不确定。我们旨在研究第四剂 COVID-19 疫苗加强针的安全性、反应原性和免疫原性。
COV-BOOST 试验是一项在英国 18 个地点进行的多中心、双盲、2 期、随机对照试验，将七种 COVID-19 疫苗作为第三剂加强针进行。这项子研究纳入了在 COV-BOOST 中接受 BNT162b2（辉瑞-生物科技）作为第三剂的参与者，并将他们随机（1:1）分配至接受第四剂 BNT162b2（30 μg 于 0.30 mL；全剂量）或 mRNA-1273（Moderna；50 μg 于 0.25 mL；半剂量）肌肉内注射，注射部位在上臂。由研究统计学家使用 2 或 4 个随机块大小创建的计算机生成随机分组列表。参与者和所有未接种疫苗的研究人员对治疗分配均设盲。主要结局是安全性和反应原性，以及免疫原性（ELISA 检测的抗刺突蛋白 IgG 滴度和 ELISpot 检测的细胞免疫反应）。我们比较了第三剂后 28 天与第四剂后 14 天，以及第四剂前 0 天与后 14 天的免疫原性。安全性和反应原性在按方案人群中进行评估，该人群包括所有接受第四剂加强针的参与者，无论其 SARS-CoV-2 血清状态如何。免疫原性主要在血清阴性且接受第四剂加强针并有终点数据的意向治疗人群中进行分析。该试验在 ISRCTN 注册，编号为 73765130，正在进行中。
在 2022 年 1 月 11 日至 1 月 25 日期间，筛查了 166 名参与者，将他们随机分配并接受全剂量 BNT162b2（n=83）或半剂量 mRNA-1273（n=83）作为第四剂。这些参与者的中位年龄为 70.1 岁（IQR 51.6-77.5），86 名（52%）参与者为女性，80 名（48%）为男性。第三剂和第四剂之间的中位间隔为 208.5 天（IQR 203.3-214.8）。在接受 BNT162b2 或 mRNA-1273 加强针后，疼痛是最常见的局部不良事件，疲劳是最常见的全身不良事件。报告的三例与 BNT162b2 相关的第四剂后严重不良事件均与研究疫苗无关。在 BNT162b2 组中，第三剂后 28 天的抗刺突蛋白 IgG 浓度几何平均值为 23325 ELISA 实验室单位（ELU）/mL（95%CI 20030-27162），在第四剂后 14 天增加至 37460 ELU/mL（31996-43857），代表显著的 fold change（几何平均值 1.59，95%CI 1.41-1.78）。与第三剂后 28 天（25317 ELU/mL，95%CI 20996-30528）相比，第四剂 mRNA-1273 后抗刺突蛋白 IgG 浓度的几何平均值显著增加（54936 ELU/mL，46826-64452），几何平均值 fold change 为 2.19（1.90-2.52）。与第四剂前（第 0 天）相比，第四剂后（第 14 天）抗刺突蛋白 IgG 滴度的 fold change 分别为 12.19（95%CI 10.37-14.32）和 15.90（12.92-19.58），分别在 BNT162b2 和 mRNA-1273 组中。在第四剂后，T 细胞反应也得到了增强（例如，第四剂后针对野生型变异的 fold change 在 BNT162b2 组中为 7.32（95%CI 3.24-16.54），在 mRNA-1273 组中为 6.22（3.90-9.92））。
第四剂 COVID-19 mRNA 加强疫苗具有良好的耐受性，并增强细胞和体液免疫。第四剂后的峰值反应与第三剂后的峰值反应相似，甚至可能更好。
英国疫苗工作组和国家卫生研究院。
