Oxford Vaccine Group, NIHR Oxford Biomedical Research Centre, Department of Paediatrics, University of Oxford, Oxford, UK.
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.
J Infect. 2023 Sep;87(3):230-241. doi: 10.1016/j.jinf.2023.06.007. Epub 2023 Jun 17.
This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents.
A phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30 µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. 'Breakthrough infection' analyses were exploratory.
148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX (adjusted geometric mean ratio [aGMR]) 1.09 95% confidence interval (CI): 0.84, 1.42] and lower for BNT-10 (aGMR 0.78 [95% CI: 0.61, 0.99]). For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 (aGMR 1.0 [95% CI: 0.65, 1.54] and 1.02 [95% CI: 0.71, 1.48], respectively), but higher for NVX (aGMR 1.7 [95% CI: 1.07, 2.69] and 1.43 [95% CI: 0.96, 2.12], respectively). Compared to BNT-30, cellular immune responses were greatest for NVX (aGMR 1.73 [95% CI: 0.94, 3.18]), and lowest for BNT-10 (aGMR 0.65 [95% CI: 0.37, 1.15]) at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported 'breakthrough infection' compared to BNT-30 (adjusted hazard ratio [aHR] 0.11 [95% CI: 0.01, 0.86]) up until day 132 after second dose. BNT-10 recipients were more likely to have a 'breakthrough infection' compared to BNT-30 (aHR 2.14 [95% CI: 1.02, 4.51]) up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules.
Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule.
National Institute for Health Research and Vaccine Task Force.
International Standard Randomised Controlled Trial Number registry: 12348322.
这是第一项研究，旨在调查青少年中异源或分剂量 COVID-19 疫苗方案的反应原性和免疫原性。
一项 II 期、单盲、多中心、随机对照试验于 2021 年 9 月至 11 月在英国的七个地点进行，随访至 2022 年 8 月。健康的 12 至 16 岁儿童随机（1:1:1）接受 30µg BNT162b2（BNT-30）、10µg BNT162b2（BNT-10）或 NVX-CoV2373（NVX），在接受 30µg BNT162b2 后的第 8 周接受第二剂。主要结局是接种后一周内的全身反应。次要结局包括免疫原性和安全性。“突破性感染”分析是探索性的。
共招募了 148 名参与者（中位年龄 14 岁，女性占 62%，26%的参与者在第二次剂量前抗核衣壳 IgG 阳性）；132 名参与者接受了第二剂。反应大多为轻度至中度，BNT-10 组的反应率较低。未发生与疫苗相关的严重不良事件。与 BNT-30 相比，第二次剂量后 28 天，NVX 组的抗刺突抗体反应与 BNT-10 组相似（调整后的几何平均比 [aGMR] 1.09 [95%CI：0.84, 1.42]），而 BNT-10 组的反应率较低（aGMR 0.78 [95%CI：0.61, 0.99]）。对于 Omicron BA.1 和 BA.2，BNT-30 组在第 28 天的中和抗体滴度与 BNT-10 组相似（aGMR 1.0 [95%CI：0.65, 1.54]和 1.02 [95%CI：0.71, 1.48]），而 NVX 组的滴度较高（aGMR 1.7 [95%CI：1.07, 2.69]和 1.43 [95%CI：0.96, 2.12]）。与 BNT-30 相比，NVX 组的细胞免疫反应最强（aGMR 1.73 [95%CI：0.94, 3.18]），而 BNT-10 组的反应最低（aGMR 0.65 [95%CI：0.37, 1.15]），在第二次剂量后第 14 天。第二次剂量后第 236 天，各研究组的细胞反应相似。在 SARS-CoV-2 感染阴性的参与者中，与 BNT-30 相比，NVX 组的“突破性感染”风险降低了 89%（调整后的危险比 [aHR] 0.11 [95%CI：0.01, 0.86]），直至第二次剂量后第 132 天。与 BNT-30 相比，BNT-10 组在第二次剂量后第 132 天和第 236 天的“突破性感染”风险更高（aHR 2.14 [95%CI：1.02, 4.51]）。第二次剂量后 132 天和 236 天的抗体反应在所有疫苗方案中相似。
青少年中异源和分剂量 COVID-19 疫苗方案是安全、耐受良好且具有免疫原性的。使用 NVX-CoV2373 进行的异源剂量方案对 Omicron SARS-CoV-2 变体的性能优于授权的同源方案，这表明该 mRNA 疫苗和蛋白亚单位加强方案可能比授权的同源方案提供更广泛的保护。
国家卫生研究院和疫苗工作队。
国际标准随机对照试验编号登记处：12348322。
