Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: Results from COV-BOOST trial

Leila Janani¹, Alasdair P S Munro², Annie Wright¹, Parvinder K Aley³, Gavin Babbage⁴, David Baxter⁵, Tanveer Bawa⁶, Sagida Bibi⁷, Marcin Bula⁸, Katrina Cathie², Krishna Chatterjee⁹, Catherine Cosgrove¹⁰, Yvanne Enever¹¹, Eva Galiza¹⁰, Anna L Goodman¹², Christopher A Green¹³, Mae Harris⁷, Alexander Hicks¹⁴, Christine E Jones², Nasir Kanji⁷, Agatha A van der Klaauw¹⁵, Vincenzo Libri¹⁶, Martin J Llewelyn¹⁷, Rebecca Mansfield¹⁸, Alastair C McGregor¹⁹, Angela M Minassian²⁰, Patrick Moore²¹, Yama F Mujadidi²², Hanane Trari Belhadef²², Kyra Holliday²³, Orod Osanlou²⁴, Rostam Osanlou²⁵, Mihaela Pacurar², Adrian Palfreeman²⁶, Karen Regan²⁷, Stephen Saich⁴, Dinesh Saralaya²⁷, Sunil Sharma¹⁷, Ray Sheridan²⁸, Matthew Stokes⁴, Emma C Thomson²⁹, Shirley Todd²⁸, Chris Twelves²³, Daniel Wright⁷, Robert C Read², Sue Charlton³⁰, Bassam Hallis³⁰, Mary Ramsay³¹, Nick Andrews³¹, Jonathan S Nguyen-Van-Tam³², Victoria Cornelius¹, Teresa Lambe⁷, Paul T Heath¹⁰, Xinxue Liu³³, Saul N Faust³⁴; COV-BOOST study group

Affiliations

¹ Imperial Clinical Trials Unit, Imperial College London, London, UK.
² 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.
³ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
⁴ NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁵ Stockport NHS Foundation Trust, Stockport, UK.
⁶ Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁷ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
⁸ NIHR Liverpool Clinical Research Facility, Liverpool, UK.
⁹ NIHR Cambridge Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁰ Institute of Infection and Immunity & Vaccine Institute, City St George's, University of London, UK; St George's University Hospitals NHS Foundation Trust, London, UK.
¹¹ PHARMExcel, Welwyn Garden City, Hertfordshire, UK.
¹² Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK; MRC Clinical Trials Unit, University College London, London, UK.
¹³ NIHR/Wellcome Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹⁴ Portsmouth Hospitals University NHS Trust, Portsmouth, UK.
¹⁵ Wellcome-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.
¹⁶ NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁷ University Hospitals Sussex NHS Foundation Trust, Brighton, UK.
¹⁸ Dorset Research Hub, Bournemouth, UK.
¹⁹ Department of Infectious Diseases and Tropical Medicine, London Northwest University Healthcare, London, UK.
²⁰ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
²¹ The Adam Practice, Poole, UK.
²² NIHR Oxford Biomedical Research Centre, Oxford, UK.
²³ NIHR Leeds Clinical Research Facility, Leeds Teaching Hospitals Trust and University of Leeds, Leeds, UK.
²⁴ Public Health Wales, Betsi Cadwaladr University Health Board, Bangor University, Bangor, UK.
²⁵ University of Liverpool, Liverpool, UK.
²⁶ University Hospitals of Leicester NHS Trust, University of Leicester, Leicester, UK.
²⁷ Bradford Institute for Health Research and Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
²⁸ Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK.
²⁹ Queen Elizabeth University Hospital, NHS Greater Glasgow & Clyde, Glasgow, UK; MRC University of Glasgow Centre for Virus Research, Glasgow, UK.
³⁰ UK Health Security Agency, Porton Down, UK.
³¹ UK Health Security Agency, Colindale, London, UK.
³² Lifespan and Population Health Unit, University of Nottingham School of Medicine, UK.
³³ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: xinxue.liu@paediatrics.ox.ac.uk.
³⁴ 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. Electronic address: s.faust@soton.ac.uk.

PMID: 40782888
DOI: 10.1016/j.jinf.2025.106576

Free article

Clinical Trial

Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: Results from COV-BOOST trial

Leila Janani et al. J Infect. 2025 Sep.

Free article

. 2025 Sep;91(3):106576.

doi: 10.1016/j.jinf.2025.106576. Epub 2025 Aug 7.

Authors

Affiliations

¹ Imperial Clinical Trials Unit, Imperial College London, London, UK.
² 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.
³ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
⁴ NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁵ Stockport NHS Foundation Trust, Stockport, UK.
⁶ Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁷ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
⁸ NIHR Liverpool Clinical Research Facility, Liverpool, UK.
⁹ NIHR Cambridge Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁰ Institute of Infection and Immunity & Vaccine Institute, City St George's, University of London, UK; St George's University Hospitals NHS Foundation Trust, London, UK.
¹¹ PHARMExcel, Welwyn Garden City, Hertfordshire, UK.
¹² Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK; MRC Clinical Trials Unit, University College London, London, UK.
¹³ NIHR/Wellcome Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹⁴ Portsmouth Hospitals University NHS Trust, Portsmouth, UK.
¹⁵ Wellcome-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.
¹⁶ NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁷ University Hospitals Sussex NHS Foundation Trust, Brighton, UK.
¹⁸ Dorset Research Hub, Bournemouth, UK.
¹⁹ Department of Infectious Diseases and Tropical Medicine, London Northwest University Healthcare, London, UK.
²⁰ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
²¹ The Adam Practice, Poole, UK.
²² NIHR Oxford Biomedical Research Centre, Oxford, UK.
²³ NIHR Leeds Clinical Research Facility, Leeds Teaching Hospitals Trust and University of Leeds, Leeds, UK.
²⁴ Public Health Wales, Betsi Cadwaladr University Health Board, Bangor University, Bangor, UK.
²⁵ University of Liverpool, Liverpool, UK.
²⁶ University Hospitals of Leicester NHS Trust, University of Leicester, Leicester, UK.
²⁷ Bradford Institute for Health Research and Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
²⁸ Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK.
²⁹ Queen Elizabeth University Hospital, NHS Greater Glasgow & Clyde, Glasgow, UK; MRC University of Glasgow Centre for Virus Research, Glasgow, UK.
³⁰ UK Health Security Agency, Porton Down, UK.
³¹ UK Health Security Agency, Colindale, London, UK.
³² Lifespan and Population Health Unit, University of Nottingham School of Medicine, UK.
³³ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: xinxue.liu@paediatrics.ox.ac.uk.
³⁴ 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. Electronic address: s.faust@soton.ac.uk.

PMID: 40782888
DOI: 10.1016/j.jinf.2025.106576

Abstract

Background: Heterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines.

Methods: Participants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020-004123-16) enroled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster.

Results: The BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083-244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5-241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954-74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53-0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9-9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8-4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17-7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules.

Conclusions: A BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens.

Keywords: BNT162b2; Booster; COVID-19; NVX-CoV2373; Novavax; Pfizer; SARS-CoV-2; Vaccine.

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Conflict of interest statement

Declaration of Competing Interest KC acts on behalf of University Hospital Southampton as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi and Valneva. She receives no personal financial payment for this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an Investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG may benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University’s revenue sharing policy. JH has received payments for presentations for AstraZeneca, Boehringer Ingelheim, Chiesi, Ciple & Teva. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca and Valneva. He receives no personal financial payment for this work. PM acts on behalf of University Hospital Southampton NHS Foundation Trust and The Adam Practice as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Novavax, Medicago and Sanofi. He received no personal financial payment for this work. JSN-V-T was seconded to the Department of Health and Social Care, England until 31st March 2022. He has subsequently received lecture fees from AstraZeneca, Sanofi Pasteur and has performed paid consultancy for Janssen and Seqirus. MR has provided post-marketing surveillance reports on vaccines for Pfizer and GSK for which a cost recover charge is made. PTH acts on behalf of City St Georges, University of London as an Investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Pfizer, Moderna, AstraZeneca, GlaxoSmithKline, Novavax, Sanofi, Minervax and Valneva vaccines. He receives no personal financial payment for this work.

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Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: Results from COV-BOOST trial

Affiliations

Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: Results from COV-BOOST trial

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources

Medical

Research Materials

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