Heterologous ChAdOx1/BNT162b2 vaccination induces stronger immune response than homologous ChAdOx1 vaccination: The pragmatic, multi-center, three-arm, partially randomized HEVACC trial
Zoltán Bánki,
Jose Mateus,
Annika Rössler,
Helena Schäfer,
David Bante,
Lydia Riepler,
Alba Grifoni,
Alessandro Sette,
Viviana Simon,
Barbara Falkensammer,
Hanno Ulmer,
Bianca Neurauter,
Wegene Borena,
Florian Krammer,
Dorothee von Laer,
Daniela Weiskopf,
Janine Kimpel,
Petra Flatscher,
Lukas Forer,
Elisabeth Graf,
Gerhard Hausberger,
Peter Heininger,
Michael Kundi,
Christine Mantinger,
Conny Ower,
Daniel Rainer,
Magdalena Sacher,
Lisa Seekircher,
Sebastian Schönherr,
Marton Szell,
Tobias Trips,
Ursula Wiedermann,
Peter Willeit,
Reinhard Würzner,
August Zabernigg
Affiliations
Zoltán Bánki
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria
Jose Mateus
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA
Annika Rössler
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria
Helena Schäfer
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria
David Bante
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria
Lydia Riepler
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria
Alba Grifoni
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA
Alessandro Sette
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA
Viviana Simon
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Barbara Falkensammer
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria
Hanno Ulmer
Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Austria
Bianca Neurauter
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria
Wegene Borena
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria
Florian Krammer
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corresponding authors.
Dorothee von Laer
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria; Corresponding authors.
Daniela Weiskopf
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Corresponding authors.
Janine Kimpel
Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Peter-Mayr-Str. 4b, 6020 Innsbruck, Austria; Corresponding authors.
Petra Flatscher
Hospital Schwaz, Schwaz, Austria
Lukas Forer
Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria
Elisabeth Graf
Hospital Kufstein, Kufstein, Austria
Gerhard Hausberger
Hospital Kufstein, Kufstein, Austria
Peter Heininger
Hospital Schwaz, Schwaz, Austria
Michael Kundi
Center for Public Health, Department of Environmental Health, Medical University of Vienna, 1090 Vienna, Austria
Christine Mantinger
Hospital Schwaz, Schwaz, Austria
Conny Ower
Hospital Innsbruck, Innsbruck, Austria
Daniel Rainer
Hospital Schwaz, Schwaz, Austria
Magdalena Sacher
Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Lisa Seekircher
Clinical Epidemiology Team, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
Sebastian Schönherr
Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria
Marton Szell
Emergency Department, Klinik Donaustadt, Langobardenstrasse 122, 1220, Vienna, Austria
Tobias Trips
Hospital Kufstein, Kufstein, Austria
Ursula Wiedermann
Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
Peter Willeit
Clinical Epidemiology Team, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, United Kingdom
Reinhard Würzner
Department of Public Health and Primary Care, University of Cambridge, United Kingdom
Summary: Background: Several COVID-19 vaccines have been approved. The mRNA vaccine from Pfizer/BioNTech (Comirnaty, BNT162b2; BNT) and the vector vaccine from AstraZeneca (Vaxzevria, ChAdOx1; AZ) have been widely used. mRNA vaccines induce high antibody and T cell responses, also to SARS-CoV-2 variants, but are costlier and less stable than the slightly less effective vector vaccines. For vector vaccines, heterologous vaccination schedules have generally proven more effective than homologous schedules. Methods: In the HEVACC three-arm, single-blinded, adaptive design study (ClinicalTrials.gov Identifier: NCT04907331), participants between 18 and 65 years with no prior history of SARS-CoV-2 infection and a first dose of AZ or BNT were included. The AZ/AZ and the AZ/BNT arms were randomized (in a 1:1 ratio stratified by sex and trial site) and single-blinded, the third arm (BNT/BNT) was observational. We compared the reactogenicity between the study arms and hypothesized that immunogenicity was higher for the heterologous AZ/BNT compared to the homologous AZ/AZ regimen using neutralizing antibody titers as primary endpoint. Findings: This interim analysis was conducted after 234 participants had been randomized and 254 immunized (N=109 AZ/AZ, N=115 AZ/BNZ, N=30 BNT/BNT). Heterologous AZ/BNT vaccination was well tolerated without study-related severe adverse events. Neutralizing antibody titers on day 30 were statistically significant higher in the AZ/BNT and the BNT/BNT groups than in the AZ/AZ group, for B.1.617.2 (Delta) AZ/AZ median reciprocal titer 75.9 (99.9% CI 58.0 - 132.5), AZ/BNT 571.5 (99.9% CI 396.6 - 733.1), and BNT/BNT 404.5 (99.9% CI 68.3 - 1024). Similarly, the frequency and multifunctionality of spike-specific T cell responses was comparable between the AZ/BNT and the BNT/BNT groups, but lower in the AZ/AZ vaccinees. Interpretation: This study clearly shows the immunogenicity and safety of heterologous AZ/BNT vaccination and encourages further studies on heterologous vaccination schedules. Funding: This work was supported by the Medical University of Innsbruck, and partially funded by NIAID contracts No. 75N9301900065, 75N93021C00016, and 75N93019C00051.
