Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study - A single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines

Robert H Shaw; Melanie Greenland; Arabella S V Stuart; Parvinder K Aley; Nick J Andrews; J Claire Cameron; Sue Charlton; Elizabeth A Clutterbuck; Andrea M Collins; Tom Darton; Tanya Dinesh; Christopher J A Duncan; Saul N Faust; Daniela M Ferreira; Adam Finn; Anna L Goodman; Christopher A Green; Bassam Hallis; Paul T Heath; Helen Hill; Teresa Lambe; Vincenzo Libri; Patrick J Lillie; Ella Morey; Yama F Mujadidi; Ruth Payne; Emma L Plested; Samuel Provstgaard-Morys; Maheshi N Ramasamy; Mary Ramsay; Robert C Read; Hannah Robinson; Gavin R Screaton; Nisha Singh; David P J Turner; Paul J Turner; Rachel White; Jonathan S Nguyen-Van-Tam; Xinxue Liu; Matthew D Snape; Com-COV2 Study Group

doi:10.1016/j.jinf.2023.03.027

Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study - A single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines

J Infect. 2023 Jun;86(6):574-583. doi: 10.1016/j.jinf.2023.03.027. Epub 2023 Apr 6.

Authors

Robert H Shaw¹, Melanie Greenland², Arabella S V Stuart³, Parvinder K Aley², Nick J Andrews⁴, J Claire Cameron⁵, Sue Charlton⁶, Elizabeth A Clutterbuck², Andrea M Collins⁷, Tom Darton⁸, Tanya Dinesh², Christopher J A Duncan⁹, Saul N Faust¹⁰, Daniela M Ferreira⁷, Adam Finn¹¹, Anna L Goodman¹², Christopher A Green¹³, Bassam Hallis⁶, Paul T Heath¹⁴, Helen Hill⁷, Teresa Lambe¹⁵, Vincenzo Libri¹⁶, Patrick J Lillie¹⁷, Ella Morey², Yama F Mujadidi², Ruth Payne⁸, Emma L Plested², Samuel Provstgaard-Morys², Maheshi N Ramasamy³, Mary Ramsay⁴, Robert C Read¹⁰, Hannah Robinson², Gavin R Screaton¹⁸, Nisha Singh², David P J Turner¹⁹, Paul J Turner²⁰, Rachel White², Jonathan S Nguyen-Van-Tam²¹, Xinxue Liu², Matthew D Snape²²; Com-COV2 Study Group

Affiliations

¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Electronic address: robert.shaw@paediatrics.ox.ac.uk.
² Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
³ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁴ Immunisation and Vaccine Preventable Diseases Division, UK Health Security Agency, London, UK.
⁵ Public Health Scotland, Glasgow, Scotland, UK.
⁶ UK Health Security Agency, Porton Down, Salisbury, UK.
⁷ Liverpool School of Tropical Medicine, Liverpool, UK.
⁸ Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, UK; Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, UK.
⁹ The Newcastle upon Tyne Hospitals NHS Foundation Trust, UK; Translational and Clinical Research Institute, Newcastle University, UK.
¹⁰ 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.
¹¹ Schools of Population Health Sciences and Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
¹² Department of Infection & NIHR BRC, Guy's and St Thomas' NHS Foundation Trust, UK; MRC Clinical Trials Unit, University College London, UK.
¹³ NIHR/Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; School of Chemical Engineering, University of Birmingham, UK.
¹⁴ The Vaccine Institute, St. George's University of London, London, UK.
¹⁵ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
¹⁶ NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁷ Infection Research Group, Hull University Teaching Hospitals NHS Trust, Hull, UK.
¹⁸ Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁹ University of Nottingham, Nottingham, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK.
²⁰ National Heart & Lung Institute, Imperial College London, London, UK.
²¹ Unit of Lifespan and Population Health, University of Nottingham School of Medicine, Nottingham, UK.
²² Oxford NIHR - Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Abstract

Background: Heterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development.

Methods: Com-COV2 was a single-blinded trial in which adults ≥ 50 years, previously immunised with single dose 'ChAd' (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or 'BNT' (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8-12 weeks later with either the homologous vaccine, or 'Mod' (mRNA-1273, Spikevax, Moderna) or 'NVX' (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration.

Findings: In April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N = 540, 45% female) or BNT (N = 532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95% CI (confidence interval): 8.2, 11.5) at D28 to 6.2 (95% CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95% CI:2.5,3.5) to 2.4 (95% CI:1.9, 3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The adjusted GMR (aGMR) for BNT/Mod compared with BNT/BNT increased from 1.36 (95% CI: 1.17, 1.58) at D28 to 1.52 (95% CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95% CI: 0.47, 0.64) at day 28 and 0.62 (95% CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies.

Interpretation: Heterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics.

Isrctn: 27841311 EudraCT:2021-001275-16.

Keywords: Adenovirus vector; Antibody; Heterologous; Persistence; SARS-CoV2; T-cell; Vaccine; mRNA lipid nanoparticle.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antibodies, Viral
BNT162 Vaccine
COVID-19 Vaccines
COVID-19* / prevention & control
ChAdOx1 nCoV-19
Female
Humans
Immunity
Immunoglobulin G
Male
Pandemics
Single-Blind Method
Vaccination
Vaccines*

Substances

COVID-19 Vaccines
ChAdOx1 nCoV-19
BNT162 Vaccine
Vaccines
Immunoglobulin G
Antibodies, Viral

Associated data

ISRCTN/ISRCTN27841311
EudraCT/2021-001275-16

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding