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Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine

View ORCID ProfileRishi R. Goel, Mark M. Painter, Kendall A. Lundgreen, View ORCID ProfileSokratis A. Apostolidis, Amy E. Baxter, Josephine R. Giles, Divij Mathew, Ajinkya Pattekar, Arnold Reynaldi, David S. Khoury, Sigrid Gouma, Philip Hicks, Sarah Dysinger, Amanda Hicks, Harsh Sharma, Sarah Herring, Scott Korte, Wumesh KC, Derek A. Oldridge, Rachel I. Erickson, Madison E. Weirick, Christopher M. McAllister, Moses Awofolaju, Nicole Tanenbaum, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Maura McLaughlin, Justine C. Williams, Sharon Adamski, Oliva Kuthuru, Elizabeth M. Drapeau, View ORCID ProfileMiles P. Davenport, View ORCID ProfileScott E. Hensley, Paul Bates, Allison R. Greenplate, E. John Wherry
doi: https://doi.org/10.1101/2022.02.20.481163
Rishi R. Goel
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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  • ORCID record for Rishi R. Goel
Mark M. Painter
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
3Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Kendall A. Lundgreen
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Sokratis A. Apostolidis
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
5Division of Rheumatology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Amy E. Baxter
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
3Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Josephine R. Giles
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
3Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
6Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Divij Mathew
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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Ajinkya Pattekar
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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Arnold Reynaldi
7Kirby Institute, University of New South Wales; Sydney, Australia
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David S. Khoury
7Kirby Institute, University of New South Wales; Sydney, Australia
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Sigrid Gouma
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Philip Hicks
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Sarah Dysinger
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Amanda Hicks
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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Harsh Sharma
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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Sarah Herring
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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Scott Korte
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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Wumesh KC
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
8Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Derek A. Oldridge
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
9Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Rachel I. Erickson
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Madison E. Weirick
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Christopher M. McAllister
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Moses Awofolaju
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Nicole Tanenbaum
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Jeanette Dougherty
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Sherea Long
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Kurt D’Andrea
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Jacob T. Hamilton
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Maura McLaughlin
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
3Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Justine C. Williams
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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Sharon Adamski
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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Oliva Kuthuru
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Elizabeth M. Drapeau
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Miles P. Davenport
7Kirby Institute, University of New South Wales; Sydney, Australia
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Scott E. Hensley
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Paul Bates
4Department of Microbiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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Allison R. Greenplate
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
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E. John Wherry
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
2Immune Health™, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USAs
3Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
6Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA
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  • For correspondence: wherry@pennmedicine.upenn.edu
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Abstract

Despite a clear role in protective immunity, the durability and quality of antibody and memory B cell responses induced by mRNA vaccination, particularly by a 3rd dose of vaccine, remains unclear. Here, we examined antibody and memory B cell responses in a cohort of individuals sampled longitudinally for ∼9-10 months after the primary 2-dose mRNA vaccine series, as well as for ∼3 months after a 3rd mRNA vaccine dose. Notably, antibody decay slowed significantly between 6- and 9-months post-primary vaccination, essentially stabilizing at the time of the 3rd dose. Antibody quality also continued to improve for at least 9 months after primary 2-dose vaccination. Spike- and RBD-specific memory B cells were stable through 9 months post-vaccination with no evidence of decline over time, and ∼40-50% of RBD-specific memory B cells were capable of simultaneously recognizing the Alpha, Beta, Delta, and Omicron variants. Omicron-binding memory B cells induced by the first 2 doses of mRNA vaccine were boosted significantly by a 3rd dose and the magnitude of this boosting was similar to memory B cells specific for other variants. Pre-3rd dose memory B cell frequencies correlated with the increase in neutralizing antibody titers after the 3rd dose. In contrast, pre-3rd dose antibody titers inversely correlated with the fold-change of antibody boosting, suggesting that high levels of circulating antibodies may limit reactivation of immunological memory and constrain further antibody boosting by mRNA vaccines. These data provide a deeper understanding of how the quantity and quality of antibody and memory B cell responses change over time and number of antigen exposures. These data also provide insight into potential immune dynamics following recall responses to additional vaccine doses or post-vaccination infections.

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Competing Interest Statement

S.E.H. has received consultancy fees from Sanofi Pasteur, Lumen, Novavax, and Merck for work unrelated to this study. A.R.G. is a consultant for Relation Therapeutics. E.J.W. is consulting for or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences. The authors declare no other competing interests.

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-ND 4.0 International license.
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Posted February 22, 2022.
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Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine
Rishi R. Goel, Mark M. Painter, Kendall A. Lundgreen, Sokratis A. Apostolidis, Amy E. Baxter, Josephine R. Giles, Divij Mathew, Ajinkya Pattekar, Arnold Reynaldi, David S. Khoury, Sigrid Gouma, Philip Hicks, Sarah Dysinger, Amanda Hicks, Harsh Sharma, Sarah Herring, Scott Korte, Wumesh KC, Derek A. Oldridge, Rachel I. Erickson, Madison E. Weirick, Christopher M. McAllister, Moses Awofolaju, Nicole Tanenbaum, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Maura McLaughlin, Justine C. Williams, Sharon Adamski, Oliva Kuthuru, Elizabeth M. Drapeau, Miles P. Davenport, Scott E. Hensley, Paul Bates, Allison R. Greenplate, E. John Wherry
bioRxiv 2022.02.20.481163; doi: https://doi.org/10.1101/2022.02.20.481163
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Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine
Rishi R. Goel, Mark M. Painter, Kendall A. Lundgreen, Sokratis A. Apostolidis, Amy E. Baxter, Josephine R. Giles, Divij Mathew, Ajinkya Pattekar, Arnold Reynaldi, David S. Khoury, Sigrid Gouma, Philip Hicks, Sarah Dysinger, Amanda Hicks, Harsh Sharma, Sarah Herring, Scott Korte, Wumesh KC, Derek A. Oldridge, Rachel I. Erickson, Madison E. Weirick, Christopher M. McAllister, Moses Awofolaju, Nicole Tanenbaum, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Maura McLaughlin, Justine C. Williams, Sharon Adamski, Oliva Kuthuru, Elizabeth M. Drapeau, Miles P. Davenport, Scott E. Hensley, Paul Bates, Allison R. Greenplate, E. John Wherry
bioRxiv 2022.02.20.481163; doi: https://doi.org/10.1101/2022.02.20.481163

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