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

David Hillus, Tatjana Schwarz, Pinkus Tober-Lau, Kanika Vanshylla, Hana Hastor, Charlotte Thibeault, Stefanie Jentzsch, Elisa T Helbig, Lena J Lippert, Patricia Tscheak, Marie Luisa Schmidt, Johanna Riege, André Solarek, Christof von Kalle, Chantip Dang-Heine, Henning Gruell, Piotr Kopankiewicz, Norbert Suttorp, Christian Drosten, Harald Bias, Joachim Seybold, EICOV/COVIM Study Group, Florian Klein, Florian Kurth, Victor Max Corman, Leif Erik Sander, Ben Al-Rim, Lara Bardtke, Jörn Ilmo Beheim-Schwarzbach, Kerstin Behn, Leon Bergfeld, Norma Bethke, Tobias Bleicker, Dana Briesemeister, Sophia Brumhard, Claudia Conrad, Sebastian Dieckmann, Doris Frey, Julie-Anne Gabelich, Philipp Georg, Ute Gläser, Lisbeth Hasler, Andreas Hetey, Anna Luisa Hiller, Alexandra Horn, Claudia Hülso, Luisa Kegel, Willi Koch, Alexander Krannich, Paolo Kroneberg, Michelle Lisy, Petra Mackeldanz, Birgit Maeß, Friederike Münn, Nadine Olk, Christian Peiser, Kai Pohl, Annelie Hermel, Maria Rönnefarth, Carolin Rubisch, Angela Sanchez Rezza, Isabelle Schellenberger, Viktoria Schenkel, Jenny Schlesinger, Sein Schmidt, Georg Schwanitz, Anne-Sophie Sinnigen, Paula Stubbemann, Julia Tesch, Denise Treue, Daniel Wendisch, Saskia Zvorc, David Hillus, Tatjana Schwarz, Pinkus Tober-Lau, Kanika Vanshylla, Hana Hastor, Charlotte Thibeault, Stefanie Jentzsch, Elisa T Helbig, Lena J Lippert, Patricia Tscheak, Marie Luisa Schmidt, Johanna Riege, André Solarek, Christof von Kalle, Chantip Dang-Heine, Henning Gruell, Piotr Kopankiewicz, Norbert Suttorp, Christian Drosten, Harald Bias, Joachim Seybold, EICOV/COVIM Study Group, Florian Klein, Florian Kurth, Victor Max Corman, Leif Erik Sander, Ben Al-Rim, Lara Bardtke, Jörn Ilmo Beheim-Schwarzbach, Kerstin Behn, Leon Bergfeld, Norma Bethke, Tobias Bleicker, Dana Briesemeister, Sophia Brumhard, Claudia Conrad, Sebastian Dieckmann, Doris Frey, Julie-Anne Gabelich, Philipp Georg, Ute Gläser, Lisbeth Hasler, Andreas Hetey, Anna Luisa Hiller, Alexandra Horn, Claudia Hülso, Luisa Kegel, Willi Koch, Alexander Krannich, Paolo Kroneberg, Michelle Lisy, Petra Mackeldanz, Birgit Maeß, Friederike Münn, Nadine Olk, Christian Peiser, Kai Pohl, Annelie Hermel, Maria Rönnefarth, Carolin Rubisch, Angela Sanchez Rezza, Isabelle Schellenberger, Viktoria Schenkel, Jenny Schlesinger, Sein Schmidt, Georg Schwanitz, Anne-Sophie Sinnigen, Paula Stubbemann, Julia Tesch, Denise Treue, Daniel Wendisch, Saskia Zvorc

Abstract

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.

Conflict of interest statement

Declaration of interests VMC is named together with Euroimmun on a patent application filed recently regarding the diagnosis of SARS-CoV-2 by antibody testing (application number EP20158626.0). HG and FKl are named on a patent application regarding neutralising antibodies against SARS-related coronaviruses (application number EP20177354). All other authors declare no competing interests.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Study profile AZ=ChAdOx1 nCov-19 COVID-19 vaccine. BNT=BNT162b2 mRNA COVID-19 vaccine. RBD=SARS-CoV-2 receptor-binding domain. S1= SARS-CoV-2 spike protein S1 domain. sVNT=surrogate virus neutralisation assay. pNT=pseudovirus neutralisation test. IGRA=interferon-γ release assay.
Figure 2
Figure 2
Local and systemic reactogenicity of BNT162b2 or ChAdOx1 nCov-19 prime immunisations and homologous or heterologous boosting until day 7 after vaccination Figure shows the proportion of participants reporting any local reaction (A) and indicated local reactions grouped by severity (B), proportion of participants reporting any systemic reaction (C) and indicated systemic symptoms grouped by severity (D), and proportion of participants reporting intake of antipyretic medication within 24 h after vaccination and prophylactic intake of antipyretic medication (E). Definition of severity according to modified US Food and Drug Administration criteria of mild (does not interfere with daily activities), moderate (interferes with daily activities), and severe (daily activities no longer feasible).
Figure 2
Figure 2
Local and systemic reactogenicity of BNT162b2 or ChAdOx1 nCov-19 prime immunisations and homologous or heterologous boosting until day 7 after vaccination Figure shows the proportion of participants reporting any local reaction (A) and indicated local reactions grouped by severity (B), proportion of participants reporting any systemic reaction (C) and indicated systemic symptoms grouped by severity (D), and proportion of participants reporting intake of antipyretic medication within 24 h after vaccination and prophylactic intake of antipyretic medication (E). Definition of severity according to modified US Food and Drug Administration criteria of mild (does not interfere with daily activities), moderate (interferes with daily activities), and severe (daily activities no longer feasible).
Figure 3
Figure 3
SARS-CoV-2-specific IgG and T-cell responses Figure shows anti-RBD IgG (A) and anti-S1 IgG (B) assays, anti-S1 IgG avidity (C), and neutralising capacity measured by sVNT (D) in serum of participants who had received prime immunisation with BNT162b2 or ChAdOx1 nCov-19, and homologous BNT162b2 or ChAdOx1 nCov-19 or heterologous ChAdOx1 nCov-19–BNT162b2 boost; serum neutralisation activity against B.1.1.7 (alpha) and B.1.351 (beta) variants measured by pNT after boost immunisation (E); and T-cell reactivity in whole blood samples measured by IGRA (F). Samples were taken before first immunisation, 3 weeks after first vaccination, and 3–4 weeks after boost vaccination. Dotted lines indicate the manufacturer's pre-specified thresholds: higher than 1 S/co for anti-RBD IgG reactivity, 40–60% for borderline avidity, higher than 60% for high avidity, higher than 30% for sVNT cutoff, and 30-fold serum dilution for the alpha variant and 10-fold dilution for the beta variant for the limit of detection for pNT. Lines indicate the median, except for pNT, where the geometric mean is shown. p values are indicated. ACE2=angiotensin-converting enzyme 2. ID50=50% inhibition dilution. IFN-γ=interferon γ. ns=not significant. pNT=pseudovirus neutralisation test. pre=sample taken before first immunisation. RBD=SARS-CoV-2 receptor-binding domain. S1=SARS-CoV-2 spike protein S1 domain. S/co=signal-to-cutoff ratio. sVNT=surrogate virus neutralisation assay.

References

    1. Committee EMAPRA. Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 vaccine (ChAdOx1-S [recombinant])—COVID-19 vaccine AstraZeneca (other viral vaccines) EPITT. 2021;24
    1. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384:2124–2130.
    1. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021;384:2092–2101.
    1. Pottegård A, Lund LC, Karlstad Ø, et al. Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study. BMJ. 2021;373
    1. Ledford H. Could mixing COVID vaccines boost immune response? Nature. 2021;590:375–376.
    1. Robert Koch Institut Mitteilung der STIKO zur COVID-19-Impfung. Impfabstand und heterologes Impfschema nach Erstimpfung mit Vaxzevria (1.7.2021) 2021.
    1. Robert Koch Institut Beschluss der STIKO zur 5. Aktualisierung der COVID-19-Impfempfehlung und die dazugehörige wissenschaftliche Begründung. 2021.
    1. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603–2615.
    1. Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet. 2021;396:1979–1993.
    1. Shaw RH, Stuart A, Greenland M, Liu X, Van-Tam JSN, Snape MD. Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data. Lancet. 2021;397:2043–2046.
    1. Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting. N Engl J Med. 2021;384:1412–1423.
    1. Thompson MG, Burgess JL, Naleway AL, et al. Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers—eight U.S. locations, December 2020-March 2021. MMWR Morb Mortal Wkly Rep. 2021;70:495–500.
    1. Mahase E. COVID-19: one dose of vaccine cuts risk of passing on infection by as much as 50%, research shows. BMJ. 2021;373
    1. Lu S. Heterologous prime-boost vaccination. Curr Opin Immunol. 2009;21:346–351.
    1. Pollard AJ, Launay O, Lelievre J-D, et al. Safety and immunogenicity of a two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Europe (EBOVAC2): a randomised, observer-blind, participant-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. 2021;21:493–506.
    1. Spencer AJ, McKay PF, Belij-Rammerstorfer S, et al. Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice. Nat Commun. 2021;12
    1. Borobia AM, Carcas AJ, Pérez-Olmeda M, et al. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet. 2021;398:121–130.
    1. Center for Biologics Evaluation and Research Toxicity grading scale for volunteers in vaccine clinical trials. 2019.
    1. Schwarz T, Tober-Lau P, Hillus D, et al. Delayed antibody and T-cell response to BNT162b2 vaccination in the elderly, Germany. Emerg Infect Dis. 2021;27:2174–2178.
    1. Vanshylla K, Di Cristanziano V, Kleipass F, et al. Kinetics and correlates of the neutralizing antibody response to SARS-CoV-2 infection in humans. Cell Host Microbe. 2021;29:917. 29.e4.
    1. Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion. Stat Sci. 2001;16:101–133.
    1. Walsh EE, Frenck RW, Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N Engl J Med. 2020;383:2439–2450.
    1. Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet. 2020;396:467–478.
    1. Krammer F, Srivastava K, Alshammary H, et al. Antibody responses in seropositive persons after a single dose of SARS-CoV-2 mRNA vaccine. N Engl J Med. 2021;384:1372–1374.
    1. University of Oxford Comparing COVID-19 vaccine schedule combinations—Com-COV2. 2021.

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