Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study,The Lancet Respiratory Medicine

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Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study
The Lancet Respiratory Medicine ( IF 76.2 ) Pub Date : 2021-08-13 , DOI: 10.1016/s2213-2600(21)00357-x
David Hillus ₁ , Tatjana Schwarz ₂ , Pinkus Tober-Lau ₁ , Kanika Vanshylla ₃ , Hana Hastor ₄ , Charlotte Thibeault ₁ , Stefanie Jentzsch ₁ , Elisa T Helbig ₁ , Lena J Lippert ₁ , Patricia Tscheak ₂ , Marie Luisa Schmidt ₂ , Johanna Riege ₂ , André Solarek ₅ , Christof von Kalle ₄ , Chantip Dang-Heine ₄ , Henning Gruell ₆ , Piotr Kopankiewicz ₇ , Norbert Suttorp ₁ , Christian Drosten ₂ , Harald Bias ₇ , Joachim Seybold ₅ , , Florian Klein ₈ , Florian Kurth ₉ , Victor Max Corman ₂ , Leif Erik Sander ₁

Affiliation

Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Institute of Virology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; German Centre for Infection Research, partner site Charité, Berlin, Germany.
Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Clinical Study Center, Berlin Institute of Health, and Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Medical Directorate, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany.
Center for Occupational Medicine, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine and Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Background

Heterologous vaccine regimens have been widely discussed as a way to mitigate intermittent supply shortages and to improve immunogenicity and safety of COVID-19 vaccines. We aimed to assess the reactogenicity and immunogenicity of heterologous immunisations with ChAdOx1 nCov-19 (AstraZeneca, Cambridge, UK) and BNT162b2 (Pfizer-BioNtech, Mainz, Germany) compared with homologous BNT162b2 and ChAdOx1 nCov-19 immunisation.

Methods

This is an interim analysis of a prospective observational cohort study enrolling health-care workers in Berlin (Germany) who received either homologous ChAdOx1 nCov-19 or heterologous ChAdOx1 nCov-19–BNT162b2 vaccination with a 10–12-week vaccine interval or homologous BNT162b2 vaccination with a 3-week vaccine interval. We assessed reactogenicity after the first and second vaccination by use of electronic questionnaires on days 1, 3, 5, and 7. Immunogenicity was measured by the presence of SARS-CoV-2-specific antibodies (full spike-IgG, S1-IgG, and RBD-IgG), by an RBD–ACE2 binding inhibition assay (surrogate SARS-CoV-2 virus neutralisation test), a pseudovirus neutralisation assay against two variants of concerns (alpha [B.1.1.7] and beta [B.1.351]), and anti-S1-IgG avidity. T-cell reactivity was measured by IFN-γ release assay.

Findings

Between Dec 27, 2020, and June 14, 2021, 380 participants were enrolled in the study, with 174 receiving homologous BNT162b2 vaccination, 38 receiving homologous ChAdOx1 nCov-19 vaccination, and 104 receiving ChAdOx1 nCov-19–BNT162b2 vaccination. Systemic symptoms were reported by 103 (65%, 95% CI 57·1–71·8) of 159 recipients of homologous BNT162b2, 14 (39%, 24·8–55·1) of 36 recipients of homologous ChAdOx1 nCov-19, and 51 (49%, 39·6–58·5) of 104 recipients of ChAdOx1 nCov-19–BNT162b2 after the booster immunisation. Median anti-RBD IgG levels 3 weeks after boost immunisation were 5·4 signal to cutoff ratio (S/co; IQR 4·8–5·9) in recipients of homologous BNT162b2, 4·9 S/co (4·3–5·6) in recipients of homologous ChAdOx1 nCov-19, and 5·6 S/co (5·1–6·1) in recipients of ChAdOx1 nCov-19– BNT162b2. Geometric mean of 50% inhibitory dose against alpha and beta variants were highest in recipients of ChAdOx1 nCov-19–BNT162b2 (956·6, 95% CI 835·6–1095, against alpha and 417·1, 349·3–498·2, against beta) compared with those in recipients of homologous ChAdOx1 nCov-19 (212·5, 131·2–344·4, against alpha and 48·5, 28·4–82·8, against beta; both p<0·0001) or homologous BNT162b2 (369·2, 310·7–438·6, against alpha and 72·4, 60·5–86·5, against beta; both p<0·0001). SARS-CoV-2 S1 T-cell reactivity 3 weeks after boost immunisation was highest in recipients of ChAdOx1 nCov-19–BNT162b2 (median IFN-γ concentration 4762 mIU/mL, IQR 2723–8403) compared with that in recipients of homologous ChAdOx1 nCov-19 (1061 mIU/mL, 599–2274, p<0·0001) and homologous BNT162b2 (2026 mIU/mL, 1459–4621, p=0·0008) vaccination.

Interpretation

The heterologous ChAdOx1 nCov-19–BNT162b2 immunisation with 10–12-week interval, recommended in Germany, is well tolerated and improves immunogenicity compared with homologous ChAdOx1 nCov-19 vaccination with 10–12-week interval and BNT162b2 vaccination with 3-week interval. Heterologous prime-boost immunisation strategies for COVID-19 might be generally applicable.

Funding

Forschungsnetzwerk der Universitätsmedizin zu COVID-19, the German Ministry of Education and Research, Zalando SE.

中文翻译：

使用 ChAdOx1 nCoV-19 和 BNT162b2 进行同源和异源初免加强免疫的安全性、反应原性和免疫原性：一项前瞻性队列研究

背景

异源疫苗方案已被广泛讨论，作为缓解间歇性供应短缺和提高 COVID-19 疫苗免疫原性和安全性的一种方法。我们的目的是评估与同源 BNT162b2 和 ChAdOx1 nCov-19 免疫相比，ChAdOx1 nCov-19（阿斯利康，英国剑桥）和 BNT162b2（辉瑞生物技术公司，美因茨，德国）异源免疫的反应原性和免疫原性。

方法

这是一项前瞻性观察性队列研究的中期分析，招募了柏林（德国）的医护人员，他们接受了同源 ChAdOx1 nCov-19 或异源 ChAdOx1 nCov-19–BNT162b2 疫苗接种，疫苗间隔为 10-12 周或同源 BNT162b2疫苗接种间隔为 3 周。我们在第 1、3、5 和 7 天使用电子问卷评估了第一次和第二次疫苗接种后的反应原性。免疫原性通过 SARS-CoV-2 特异性抗体（全刺突 IgG、S1-IgG、和 RBD-IgG），通过 RBD–ACE2 结合抑制试验（替代 SARS-CoV-2 病毒中和试验），一种针对两种关注变体（α [B.1.1.7] 和β [B.1.351] 的假病毒中和试验]), 和抗 S1-IgG 亲和力。通过 IFN-γ 释放测定法测量 T 细胞反应性。

发现

2020 年 12 月 27 日至 2021 年 6 月 14 日期间，380 名参与者参加了该研究，其中 174 人接受了同源 BNT162b2 疫苗接种，38 人接受了同源 ChAdOx1 nCov-19 疫苗接种，104 人接受了 ChAdOx1 nCov-19–BNT162b2 疫苗接种。159 名同源 BNT162b2 接受者中有 103 名（65%，95% CI 57·1–71·8）报告了全身症状，36 名同源 ChAdOx1 nCov-19 接受者中有 14 名（39%，24·8–55·1）报告了全身症状, 和 104 名 ChAdOx1 nCov-19–BNT162b2 接受者中的 51 名 (49%, 39·6–58·5) 在加强免疫后。加强免疫后 3 周的中位抗 RBD IgG 水平在同源 BNT162b2、4·9 S/co (4·3– 5·6) 在同源 ChAdOx1 nCov-19 的接受者中，5·6 S/co (5·1–6·1) 在 ChAdOx1 nCov-19– BNT162b2 的接受者中。在 ChAdOx1 nCov-19–BNT162b2 接受者中，针对 alpha 和 beta 变体的 50% 抑制剂量的几何平均值最高（956·6，95% CI 835·6–1095，针对 alpha 和 417·1，349·3–498· 2, against beta) 与同源 ChAdOx1 nCov-19 接受者相比（212·5, 131·2–344·4, against alpha 和 48·5, 28·4–82·8, against beta; p< 0·0001) 或同源 BNT162b2（369·2、310·7–438·6，针对 alpha 和 72·4、60·5–86·5，针对 beta；均 p<0·0001）。与同源 ChAdOx1 接受者相比，ChAdOx1 nCov-19–BNT162b2 接受者在加强免疫后 3 周的 SARS-CoV-2 S1 T 细胞反应性最高（中位 IFN-γ 浓度 4762 mIU/mL，IQR 2723–8403） nCov-19 (1061 mIU/mL, 599–2274, p<0·0001) 和同源 BNT162b2 (2026 mIU/mL, 1459–4621, p=0·0008) 疫苗接种。

解释

德国推荐的间隔 10-12 周的异源 ChAdOx1 nCov-19-BNT162b2 免疫接种与间隔 10-12 周的同源 ChAdOx1 nCov-19 疫苗接种和间隔 3 周的 BNT162b2 疫苗接种相比具有良好的耐受性并提高了免疫原性. 针对 COVID-19 的异源初免-加强免疫策略可能普遍适用。