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mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern

View ORCID ProfileRishi R. Goel, Mark M. Painter, Sokratis A. Apostolidis, Divij Mathew, Wenzhao Meng, Aaron M. Rosenfeld, Kendall A. Lundgreen, Arnold Reynaldi, David S. Khoury, Ajinkya Pattekar, Sigrid Gouma, Leticia Kuri-Cervantes, Philip Hicks, Sarah Dysinger, Amanda Hicks, Harsh Sharma, Sarah Herring, Scott Korte, Amy E. Baxter, Derek A. Oldridge, Josephine R. Giles, Madison E. Weirick, Christopher M. McAllister, Moses Awofolaju, Nicole Tanenbaum, Elizabeth M. Drapeau, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Maura McLaughlin, Justine C. Williams, Sharon Adamski, Oliva Kuthuru, The UPenn COVID Processing Unit, Ian Frank, Michael R. Betts, Laura A. Vella, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Scott E. Hensley, Miles P. Davenport, Paul Bates, Eline T. Luning Prak, Allison R. Greenplate, E. John Wherry
doi: https://doi.org/10.1101/2021.08.23.457229
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
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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
3Division of Rheumatology, 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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Wenzhao Meng
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
4Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Aaron M. Rosenfeld
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
4Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Kendall A. Lundgreen
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Arnold Reynaldi
6Kirby Institute, University of New South Wales, Sydney, Australia
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David S. Khoury
6Kirby Institute, University of New South Wales, Sydney, Australia
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Ajinkya Pattekar
2Immune Health™, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USAs
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Sigrid Gouma
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Leticia Kuri-Cervantes
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Philip Hicks
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Sarah Dysinger
5Department 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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Amy E. Baxter
1Institute for Immunology, 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
4Department of Pathology and Laboratory Medicine, 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
7Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
8Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Madison E. Weirick
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Christopher M. McAllister
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Moses Awofolaju
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Nicole Tanenbaum
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Elizabeth M. Drapeau
5Department 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
5Department 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
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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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Ian Frank
9Division of Infectious Disease, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Michael R. Betts
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Laura A. Vella
10Division of Infectious Disease, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
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Alba Grifoni
11Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA
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Daniela Weiskopf
11Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA
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Alessandro Sette
11Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA
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Scott E. Hensley
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Miles P. Davenport
6Kirby Institute, University of New South Wales, Sydney, Australia
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Paul Bates
5Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Eline T. Luning Prak
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
4Department of Pathology and Laboratory Medicine, 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
7Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
8Parker 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

SARS-CoV-2 mRNA vaccines have shown remarkable efficacy, especially in preventing severe illness and hospitalization. However, the emergence of several variants of concern and reports of declining antibody levels have raised uncertainty about the durability of immune memory following vaccination. In this study, we longitudinally profiled both antibody and cellular immune responses in SARS-CoV-2 naïve and recovered individuals from pre-vaccine baseline to 6 months post-mRNA vaccination. Antibody and neutralizing titers decayed from peak levels but remained detectable in all subjects at 6 months post-vaccination. Functional memory B cell responses, including those specific for the receptor binding domain (RBD) of the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants, were also efficiently generated by mRNA vaccination and continued to increase in frequency between 3 and 6 months post-vaccination. Notably, most memory B cells induced by mRNA vaccines were capable of cross-binding variants of concern, and B cell receptor sequencing revealed significantly more hypermutation in these RBD variant-binding clones compared to clones that exclusively bound wild-type RBD. Moreover, the percent of variant cross-binding memory B cells was higher in vaccinees than individuals who recovered from mild COVID-19. mRNA vaccination also generated antigen-specific CD8+ T cells and durable memory CD4+ T cells in most individuals, with early CD4+ T cell responses correlating with humoral immunity at later timepoints. These findings demonstrate robust, multi-component humoral and cellular immune memory to SARS-CoV-2 and current variants of concern for at least 6 months after mRNA vaccination. Finally, we observed that boosting of pre-existing immunity with mRNA vaccination in SARS-CoV-2 recovered individuals primarily increased antibody responses in the short-term without significantly altering antibody decay rates or long-term B and T cell memory. Together, this study provides insights into the generation and evolution of vaccine-induced immunity to SARS-CoV-2, including variants of concern, and has implications for future booster strategies.

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Competing Interest Statement

AS is a consultant for Gritstone, Flow Pharma, CellCarta, Arcturus, Oxfordimmunotech, and Avalia. La Jolla Institute for Immunology has filed for patent protection for various aspects of T cell epitope and vaccine design work. SEH has received consultancy fees from Sanofi Pasteur, Lumen, Novavax, and Merk for work unrelated to this report. ELP is consulting or an advisor for Roche Diagnostics, Enpicom, The Antibody Society, IEDB, and The American Autoimmune Related Diseases Association. EJW is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine and Surface Oncology. EJW is a founder of Surface Oncology, Danger Bio and Arsenal Biosciences. EJW is an inventor on a patent (US Patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer.

Footnotes

  • ↵# Members of the UPenn COVID Processing Unit are listed in the acknowledgments

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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mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern
Rishi R. Goel, Mark M. Painter, Sokratis A. Apostolidis, Divij Mathew, Wenzhao Meng, Aaron M. Rosenfeld, Kendall A. Lundgreen, Arnold Reynaldi, David S. Khoury, Ajinkya Pattekar, Sigrid Gouma, Leticia Kuri-Cervantes, Philip Hicks, Sarah Dysinger, Amanda Hicks, Harsh Sharma, Sarah Herring, Scott Korte, Amy E. Baxter, Derek A. Oldridge, Josephine R. Giles, Madison E. Weirick, Christopher M. McAllister, Moses Awofolaju, Nicole Tanenbaum, Elizabeth M. Drapeau, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Maura McLaughlin, Justine C. Williams, Sharon Adamski, Oliva Kuthuru, The UPenn COVID Processing Unit, Ian Frank, Michael R. Betts, Laura A. Vella, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Scott E. Hensley, Miles P. Davenport, Paul Bates, Eline T. Luning Prak, Allison R. Greenplate, E. John Wherry
bioRxiv 2021.08.23.457229; doi: https://doi.org/10.1101/2021.08.23.457229
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mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern
Rishi R. Goel, Mark M. Painter, Sokratis A. Apostolidis, Divij Mathew, Wenzhao Meng, Aaron M. Rosenfeld, Kendall A. Lundgreen, Arnold Reynaldi, David S. Khoury, Ajinkya Pattekar, Sigrid Gouma, Leticia Kuri-Cervantes, Philip Hicks, Sarah Dysinger, Amanda Hicks, Harsh Sharma, Sarah Herring, Scott Korte, Amy E. Baxter, Derek A. Oldridge, Josephine R. Giles, Madison E. Weirick, Christopher M. McAllister, Moses Awofolaju, Nicole Tanenbaum, Elizabeth M. Drapeau, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Maura McLaughlin, Justine C. Williams, Sharon Adamski, Oliva Kuthuru, The UPenn COVID Processing Unit, Ian Frank, Michael R. Betts, Laura A. Vella, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Scott E. Hensley, Miles P. Davenport, Paul Bates, Eline T. Luning Prak, Allison R. Greenplate, E. John Wherry
bioRxiv 2021.08.23.457229; doi: https://doi.org/10.1101/2021.08.23.457229

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