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Third dose COVID-19 mRNA vaccine enhances IgG4 isotype switching and recognition of Omicron subvariants by memory B cells after mRNA but not adenovirus priming

View ORCID ProfileGemma E. Hartley, View ORCID ProfileHolly A. Fryer, View ORCID ProfilePaul A. Gill, View ORCID ProfileIrene Boo, Scott J. Bornheimer, View ORCID ProfileP. Mark Hogarth, View ORCID ProfileHeidi E. Drummer, View ORCID ProfileRobyn E. O’Hehir, View ORCID ProfileEmily S.J. Edwards, View ORCID ProfileMenno C. van Zelm
doi: https://doi.org/10.1101/2023.09.15.557929
Gemma E. Hartley
1Allergy and Clinical Immunology Laboratory, Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia
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  • ORCID record for Gemma E. Hartley
Holly A. Fryer
1Allergy and Clinical Immunology Laboratory, Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia
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Paul A. Gill
1Allergy and Clinical Immunology Laboratory, Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia
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Irene Boo
2Viral Entry and Vaccines Group, Burnet Institute, Melbourne, VIC, Australia
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Scott J. Bornheimer
3BD Biosciences, San Jose, CA, USA
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P. Mark Hogarth
1Allergy and Clinical Immunology Laboratory, Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia
4Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
5Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
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Heidi E. Drummer
2Viral Entry and Vaccines Group, Burnet Institute, Melbourne, VIC, Australia
6Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
7Department of Microbiology, Monash University, Clayton, VIC, Australia
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Robyn E. O’Hehir
1Allergy and Clinical Immunology Laboratory, Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia
8Allergy, Asthma and Clinical Immunology Service, Alfred Hospital, Melbourne, VIC, Australia
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Emily S.J. Edwards
1Allergy and Clinical Immunology Laboratory, Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia
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Menno C. van Zelm
1Allergy and Clinical Immunology Laboratory, Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia
8Allergy, Asthma and Clinical Immunology Service, Alfred Hospital, Melbourne, VIC, Australia
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  • For correspondence: menno.vanzelm@monash.edu
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ABSTRACT

Background Booster vaccinations are recommended to improve protection against severe disease from SARS-CoV-2 infection. With primary vaccinations involving various adenoviral vector and mRNA-based formulations, it remains unclear if these differentially affect the immune response to booster doses. We here examined the effects of homologous (mRNA/mRNA) and heterologous (adenoviral vector/mRNA) vaccination on antibody and memory B cell (Bmem) responses against ancestral and Omicron subvariants.

Methods Healthy adults who received primary BNT162b2 (mRNA) (n=18) or ChAdOx1 (vector) (n=25) vaccination were sampled 1-month and 6-months after their 2nd and 3rd dose (homologous or heterologous) vaccination. Recombinant spike receptor-binding domain (RBD) proteins from ancestral, Omicron BA.2 and BA.5 variants were produced for ELISA-based serology, and tetramerized for immunophenotyping of RBD-specific Bmem.

Results Dose 3 boosters significantly increased ancestral RBD-specific plasma IgG and Bmem in both cohorts. Up to 80% of ancestral RBD-specific Bmem expressed IgG1+. IgG4+ Bmem were detectable after primary mRNA vaccination, and expanded significantly to 5-20% after dose 3, whereas heterologous boosting did not elicit IgG4+ Bmem. Recognition of Omicron BA.2 and BA.5 by ancestral RBD-specific plasma IgG increased from 20% to 60% after the 3rd dose in both cohorts. Reactivity of ancestral RBD-specific Bmem to Omicron BA.2 and BA.5 increased following a homologous booster from 40% to 60%, but not after a heterologous booster.

Conclusion A 3rd mRNA dose generates similarly robust serological and Bmem responses in homologous and heterologous vaccination groups. The expansion of IgG4+ Bmem after mRNA priming might result from the unique vaccine formulation or dosing schedule affecting the Bmem response duration and antibody maturation.

Competing Interest Statement

MCvZ, REOH and PMH are inventors on a patent application related to this work. SJB is an employee of and owns stock in BD. All the other authors declare no conflict of interest.

Footnotes

  • The title contained an extra word, 'with', that was out of context and a remnant from draft version editing. This word has been removed from the online title field and the manuscript files. Nothing else has been changed.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 19, 2023.
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Third dose COVID-19 mRNA vaccine enhances IgG4 isotype switching and recognition of Omicron subvariants by memory B cells after mRNA but not adenovirus priming
Gemma E. Hartley, Holly A. Fryer, Paul A. Gill, Irene Boo, Scott J. Bornheimer, P. Mark Hogarth, Heidi E. Drummer, Robyn E. O’Hehir, Emily S.J. Edwards, Menno C. van Zelm
bioRxiv 2023.09.15.557929; doi: https://doi.org/10.1101/2023.09.15.557929
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Third dose COVID-19 mRNA vaccine enhances IgG4 isotype switching and recognition of Omicron subvariants by memory B cells after mRNA but not adenovirus priming
Gemma E. Hartley, Holly A. Fryer, Paul A. Gill, Irene Boo, Scott J. Bornheimer, P. Mark Hogarth, Heidi E. Drummer, Robyn E. O’Hehir, Emily S.J. Edwards, Menno C. van Zelm
bioRxiv 2023.09.15.557929; doi: https://doi.org/10.1101/2023.09.15.557929

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