Background

Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines.

Methods

Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139.

Findings

Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation.

Interpretation

Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.

Funding

UK Vaccine Task Force and National Institute for Health Research.

中文翻译：

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使用腺病毒载体和 mRNA COVID-19 疫苗 (Com-COV) 的异源与同源初免加强计划的安全性和免疫原性：单盲、随机、非劣效性试验

背景

使用异源 prime-boost COVID-19 疫苗计划可以促进大规模 COVID-19 免疫接种。然而，我们之前曾报道过，包含腺病毒载体疫苗（ChAdOx1 nCoV-19，AstraZeneca；以下简称 ChAd）和 mRNA 疫苗（BNT162b2，Pfizer–BioNTech；以下简称 BNT）的异源疫苗接种程序为期 4 周间隔比同源时间表更具反应性。在这里，我们报告了使用 ChAd 和 BNT 疫苗的异源程序的安全性和免疫原性。

方法

Com-COV 是一项评估疫苗安全性、反应原性和免疫原性的参与者盲化、随机、非劣效性试验。年龄在 50 岁及以上、没有合并症或合并症得到很好控制并且之前没有通过实验室确认感染 SARS-CoV-2 的成年人符合条件，并在英国的八个地点招募。大多数符合条件的参与者被纳入一般队列（28 天或 84 天初免-加强间隔），他们被随机分配（1:1:1:1:1:1:1:1）接受 ChAd/ ChAd、ChAd/BNT、BNT/BNT 或 BNT/ChAd，以 28 天或 84 天的初免-加强间隔给药。一小部分符合条件的参与者 (n=100) 被纳入免疫学队列，他们进行了额外的血液测试以评估免疫反应；这些参与者被随机分配 (1:1:1:1) 到四个时间表（仅 28 天间隔）。参与者对接种的疫苗设盲，但对初免-加强间隔设盲。主要终点是加强后 28 天血清 SARS-CoV-2 抗尖峰 IgG 浓度（通过 ELISA 测量）的几何平均比值 (GMR)，比较 ChAd/BNT 与 ChAd/ChAd，以及 BNT/ChAd 与 BNT /BNT。如果这些比较的 GMR 的单侧 97·5% CI 下限大于 0·63，则认为异源方案不劣于批准的同源方案。主要分析是在符合方案人群中进行的，他们在基线时呈血清反应阴性。在接受至少一剂研究疫苗的参与者中进行了安全性分析。该试验已在 ISRCTN 注册，注册号为 69254139。主要终点是加强后 28 天血清 SARS-CoV-2 抗尖峰 IgG 浓度（通过 ELISA 测量）的几何平均比值 (GMR)，比较 ChAd/BNT 与 ChAd/ChAd，以及 BNT/ChAd 与 BNT /BNT。如果这些比较的 GMR 的单侧 97·5% CI 下限大于 0·63，则认为异源方案不劣于批准的同源方案。主要分析是在符合方案人群中进行的，他们在基线时呈血清反应阴性。在接受至少一剂研究疫苗的参与者中进行了安全性分析。该试验已在 ISRCTN 注册，注册号为 69254139。主要终点是加强后 28 天血清 SARS-CoV-2 抗尖峰 IgG 浓度（通过 ELISA 测量）的几何平均比值 (GMR)，比较 ChAd/BNT 与 ChAd/ChAd，以及 BNT/ChAd 与 BNT /BNT。如果这些比较的 GMR 的单侧 97·5% CI 下限大于 0·63，则认为异源方案不劣于批准的同源方案。主要分析是在符合方案人群中进行的，他们在基线时呈血清反应阴性。在接受至少一剂研究疫苗的参与者中进行了安全性分析。该试验已在 ISRCTN 注册，注册号为 69254139。如果这些比较的 GMR 的单侧 97·5% CI 下限大于 0·63，则认为异源方案不劣于批准的同源方案。主要分析是在符合方案人群中进行的，他们在基线时呈血清反应阴性。在接受至少一剂研究疫苗的参与者中进行了安全性分析。该试验已在 ISRCTN 注册，注册号为 69254139。如果这些比较的 GMR 的单侧 97·5% CI 下限大于 0·63，则认为异源方案不劣于批准的同源方案。主要分析是在符合方案人群中进行的，他们在基线时呈血清反应阴性。在接受至少一剂研究疫苗的参与者中进行了安全性分析。该试验已在 ISRCTN 注册，注册号为 69254139。

发现

在 2021 年 2 月 11 日至 2 月 26 日期间，830 名参与者被纳入并随机分组，其中包括 463 名参与者，间隔为 28 天的初免-加强剂量，此处报告了他们的结果。参与者的平均年龄为 57·8 岁 (SD 4·7)，其中 212 名 (46%) 女性参与者和 117 名 (25%) 来自少数民族。在加强后第 28 天，ChAd/BNT 接受者中 SARS-CoV-2 抗尖峰 IgG 的几何平均浓度（12 906 ELU/mL）不劣于 ChAd/ChAd 接受者（1392 ELU/mL）， GMR 为 9·2（单侧 97·5% CI 7·5 至 ∞）。在使用 BNT 启动的参与者中，我们没有显示异源程序（BNT/ChAd，7133 ELU/mL）相对于同源程序（BNT/BNT，14080 ELU/mL）的非劣效性，GMR 为 0·51 （单侧 97·5% CI 0·43 至 ∞）。所有组均发生四次严重不良事件，

解释

尽管 BNT/ChAd 方案不符合非劣效性标准，但两种异源方案的 SARS-CoV-2 抗尖峰 IgG 浓度均高于经许可的疫苗方案（ChAd/ChAd），已证明对 COVID-19 疾病有效和住院。与 ChAD/ChAd 相比，ChAd/BNT 具有更高的免疫原性，这些数据支持使用 ChAd 和 BNT COVID-19 疫苗灵活使用异源初免-加强疫苗接种。

资金

英国疫苗工作组和国家卫生研究所。