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Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination

View ORCID ProfileMark M. Painter, View ORCID ProfileDivij Mathew, View ORCID ProfileRishi R. Goel, View ORCID ProfileSokratis A. Apostolidis, Ajinkya Pattekar, Oliva Kuthuru, Amy E. Baxter, Ramin S. Herati, Derek A. Oldridge, View ORCID ProfileSigrid Gouma, Philip Hicks, Sarah Dysinger, Kendall A. Lundgreen, View ORCID ProfileLeticia Kuri-Cervantes, Sharon Adamski, Amanda Hicks, Scott Korte, Josephine R. Giles, Madison E. Weirick, Christopher M. McAllister, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Michael R. Betts, Paul Bates, View ORCID ProfileScott E. Hensley, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, View ORCID ProfileAllison R. Greenplate, View ORCID ProfileE. John Wherry
doi: https://doi.org/10.1101/2021.04.21.440862
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, 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, USA
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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, 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, USA
3Division of Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Ajinkya Pattekar
2Immune Health™, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Oliva Kuthuru
1Institute for Immunology, 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
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Ramin S. Herati
4NYU Langone Vaccine Center, Department of Medicine, New York University School of Medicine, New York, NY
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Derek A. Oldridge
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
5Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Sigrid Gouma
6Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Philip Hicks
6Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Sarah Dysinger
6Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Kendall A. Lundgreen
6Department 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
6Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Sharon Adamski
2Immune Health™, 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, USA
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Scott Korte
2Immune Health™, 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
6Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Christopher M. McAllister
6Department 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, USA
6Department of Microbiology, 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
6Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Paul Bates
6Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Scott E. Hensley
6Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Alba Grifoni
9Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA
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Daniela Weiskopf
9Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA
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Alessandro Sette
9Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, 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, USA
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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, 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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  • For correspondence: wherry@pennmedicine.upenn.edu
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Summary

The SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses in healthy individuals following mRNA vaccination. Vaccination induced rapid near-maximal antigen-specific CD4+ T cell responses in all subjects after the first vaccine dose. CD8+ T cell responses developed gradually after the first and second dose and were variable. Vaccine-induced T cells had central memory characteristics and included both Tfh and Th1 subsets, similar to natural infection. Th1 and Tfh responses following the first dose predicted post-boost CD8+ T cell and neutralizing antibody levels, respectively. Integrated analysis of 26 antigen-specific T cell and humoral responses revealed coordinated features of the immune response to vaccination. Lastly, whereas booster vaccination improved CD4+ and CD8+ T cell responses in SARS-CoV-2 naïve subjects, the second vaccine dose had little effect on T cell responses in SARS-CoV-2 recovered individuals. Thus, longitudinal analysis revealed robust T cell responses to mRNA vaccination and highlighted early induction of antigen-specific CD4+ T cells.

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Competing Interest Statement

ELP is consulting or an advisor for Roche Diagnostics, Enpicom, The Antibody Society, IEDB, and The American Autoimmune Related Diseases Association. SEH has received consultancy fees from Sanofi Pasteur, Lumen, Novavax, and Merk for work unrelated to this report. EJW is consulting or is an advisor for Merck, Elstar, Janssen, Related Sciences, Synthekine and Surface Oncology. EJW is a founder of Surface Oncology 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. 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.

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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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Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination
Mark M. Painter, Divij Mathew, Rishi R. Goel, Sokratis A. Apostolidis, Ajinkya Pattekar, Oliva Kuthuru, Amy E. Baxter, Ramin S. Herati, Derek A. Oldridge, Sigrid Gouma, Philip Hicks, Sarah Dysinger, Kendall A. Lundgreen, Leticia Kuri-Cervantes, Sharon Adamski, Amanda Hicks, Scott Korte, Josephine R. Giles, Madison E. Weirick, Christopher M. McAllister, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Michael R. Betts, Paul Bates, Scott E. Hensley, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Allison R. Greenplate, E. John Wherry
bioRxiv 2021.04.21.440862; doi: https://doi.org/10.1101/2021.04.21.440862
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Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination
Mark M. Painter, Divij Mathew, Rishi R. Goel, Sokratis A. Apostolidis, Ajinkya Pattekar, Oliva Kuthuru, Amy E. Baxter, Ramin S. Herati, Derek A. Oldridge, Sigrid Gouma, Philip Hicks, Sarah Dysinger, Kendall A. Lundgreen, Leticia Kuri-Cervantes, Sharon Adamski, Amanda Hicks, Scott Korte, Josephine R. Giles, Madison E. Weirick, Christopher M. McAllister, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Michael R. Betts, Paul Bates, Scott E. Hensley, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Allison R. Greenplate, E. John Wherry
bioRxiv 2021.04.21.440862; doi: https://doi.org/10.1101/2021.04.21.440862

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