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Antigen presentation dynamics shape the response to emergent variants like SARS-CoV-2 Omicron strain after multiple vaccinations with wild type strain

Leerang Yang, Matthew Van Beek, Zijun Wang, Frauke Muecksch, Marie Canis, Theodora Hatziioannou, Paul D. Bieniasz, Michel C. Nussenzweig, Arup K. Chakraborty
doi: https://doi.org/10.1101/2022.08.24.505127
Leerang Yang
1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Matthew Van Beek
1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Zijun Wang
2Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
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Frauke Muecksch
3Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Marie Canis
3Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Theodora Hatziioannou
3Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Paul D. Bieniasz
3Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
4Howard Hughes Medical Institute.
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Michel C. Nussenzweig
2Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
4Howard Hughes Medical Institute.
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  • For correspondence: arupc@mit.edu nussen@mail.rockefeller.edu
Arup K. Chakraborty
1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
5Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.
6Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
7Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02139.
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  • For correspondence: arupc@mit.edu nussen@mail.rockefeller.edu
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Summary

The Omicron variant of SARS-CoV-2 evades neutralization by most serum antibodies elicited by two doses of mRNA vaccines, but a third dose of the same vaccine increases anti-Omicron neutralizing antibodies. By combining computational modeling with data from vaccinated humans we reveal mechanisms underlying this observation. After the first dose, limited antigen availability in germinal centers results in a response dominated by B cells with high germline affinities for immunodominant epitopes that are significantly mutated in an Omicron-like variant. After the second dose, expansion of these memory cells and differentiation into plasma cells shape antibody responses that are thus ineffective for such variants. However, in secondary germinal centers, pre-existing higher affinity antibodies mediate enhanced antigen presentation and they can also partially mask dominant epitopes. These effects generate memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies.

Competing Interest Statement

The authors have no competing interests. For completeness, it is noted that AKC is a consultant (titled Academic Partner) for Flagship Pioneering and also serves on the Strategic Oversight Board of its affiliated company, Apriori Bio, and is a consultant and SAB member of another affiliated company, FL72. MCN is on the SAB of Celldex, Walking Fish, and Frontier Bio.

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 August 25, 2022.
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Antigen presentation dynamics shape the response to emergent variants like SARS-CoV-2 Omicron strain after multiple vaccinations with wild type strain
Leerang Yang, Matthew Van Beek, Zijun Wang, Frauke Muecksch, Marie Canis, Theodora Hatziioannou, Paul D. Bieniasz, Michel C. Nussenzweig, Arup K. Chakraborty
bioRxiv 2022.08.24.505127; doi: https://doi.org/10.1101/2022.08.24.505127
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Antigen presentation dynamics shape the response to emergent variants like SARS-CoV-2 Omicron strain after multiple vaccinations with wild type strain
Leerang Yang, Matthew Van Beek, Zijun Wang, Frauke Muecksch, Marie Canis, Theodora Hatziioannou, Paul D. Bieniasz, Michel C. Nussenzweig, Arup K. Chakraborty
bioRxiv 2022.08.24.505127; doi: https://doi.org/10.1101/2022.08.24.505127

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