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.
Imperial Clinical Trials Unit, Imperial College London, London, UK.
Lancet. 2021 Dec 18;398(10318):2258-2276. doi: 10.1016/S0140-6736(21)02717-3. Epub 2021 Dec 2.
Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT).
COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130.
Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273.
All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination.
UK Vaccine Taskforce and National Institute for Health Research.
关于不同的 COVID-19 疫苗作为加强针（第三针）接种的安全性和免疫原性比较，数据有限。为了生成优化选择加强疫苗的数据，我们研究了 ChAdOx1 nCov-19（牛津-阿斯利康；以下简称 ChAd）或 BNT162b2（辉瑞-生物技术，以下简称 BNT）两剂疫苗接种后，七种不同的 COVID-19 疫苗作为第三剂加强针的反应原性和免疫原性。
COV-BOOST 是一项多中心、随机、对照、2 期试验，旨在对 COVID-19 进行第三剂加强疫苗接种。参与者年龄大于 30 岁，距 ChAd 或 BNT 初级 COVID-19 免疫接种疗程至少 70 天，无实验室确诊的 SARS-CoV-2 感染史。18 个站点分为三组（A、B 和 C）。在每个站点组（A、B 或 C）中，参与者被随机分配到实验组疫苗或对照组。组 A 接受 NVX-CoV2373（诺瓦瓦克斯；以下简称 NVX）、NVX 半剂量、ChAd 或四价脑膜炎球菌结合疫苗（MenACWY）对照组（1:1:1:1）。组 B 接受 BNT、VLA2001（瓦伦瓦；以下简称 VLA）、VLA 半剂量、Ad26.COV2.S（杨森；以下简称 Ad26）或 MenACWY（1:1:1:1:1）。组 C 接受 mRNA1273（Moderna；以下简称 m1273）、CVnCov（CureVac；以下简称 CVn）、BNT 半剂量或 MenACWY（1:1:1:1）。参与者和所有调查人员对治疗分配均不知情。主要结局是通过 ELISA 测量的抗刺突 IgG 的安全性、反应原性和免疫原性。免疫原性的主要分析是基于改良的意向治疗原则；安全性和反应原性在意向治疗人群中进行评估。次要结局包括评估病毒中和和细胞反应。该试验在 ISRCTN 注册，编号为 73765130。
在 2021 年 6 月 1 日至 6 月 30 日期间，对 3498 人进行了筛选。2878 名符合入选标准并接受 COVID-19 疫苗或对照的参与者。ChAd/ChAd 初免参与者的中位年龄为 53 岁（四分位距 44-61），年龄较大组为 76 岁（73-78）。在 BNT/BNT 初免参与者中，年龄较小组的中位年龄为 51 岁（41-59），年龄较大组为 78 岁（75-82）。在 ChAd/ChAD 初免组中，676 名（46.7%）参与者为女性，1380 名（95.4%）为白人，在 BNT/BNT 初免组中，770 名（53.6%）参与者为女性，1321 名（91.9%）为白人。三种疫苗的总体反应原性增加：ChAd/ChAd 或 BNT/BNT 后 m1273；以及 BNT/BNT 后 ChAd 和 Ad26。对于 ChAd/ChAd 初免者，研究疫苗与对照组之间的刺突 IgG 几何平均比值（GMR）在 VLA 半剂量组为 1.8（99%CI 1.5-2.3），在 m1273 组为 32.3（24.8-42.0）。与对照组相比，野生型细胞反应的 GMR 范围为 ChAd 的 1.1（99%CI 0.7-1.6）至 m1273 的 3.6（2.4-5.5）。对于 BNT/BNT 初免者，刺突 IgG GMR 范围在 VLA 半剂量组为 1.3（99%CI 1.0-1.5），在 m1273 组为 11.5（9.4-14.1）。与对照组相比，野生型细胞反应的 GMR 范围为 VLA 的 1.0（99%CI 0.7-1.6）至 m1273 的 4.7（3.1-7.1）。年龄在 30-69 岁和 70 岁及以上的人群中，结果相似。疲劳和疼痛是最常见的局部和全身不良事件，在 30-69 岁的人群中比 70 岁及以上的人群更常见。严重不良事件并不常见，在活性疫苗和对照组中相似。共有 24 例严重不良事件：对照组 5 例（对照组 A 2 例，对照组 B3 例，对照组 C 0 例），Ad26 2 例，VLA 5 例，VLA 半剂量 1 例，BNT 1 例，BNT 半剂量 2 例，ChAd 2 例，CVn 1 例，NVX 2 例，NVX 半剂量 2 例，m1273 1 例。
所有研究疫苗在 ChAd/ChAd 初始疗程后均增强了抗体和中和反应，除一种外，所有疫苗在 BNT/BNT 后也增强了抗体和中和反应，没有安全问题。体液和细胞反应的显著差异，以及疫苗的可获得性将影响加强疫苗接种的政策选择。
英国疫苗工作组和国家卫生研究院。
