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Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies

View ORCID ProfileAngela M. Phillips, Katherine R. Lawrence, Alief Moulana, Thomas Dupic, Jeffrey Chang, Milo S. Johnson, Ivana Cvijović, Thierry Mora, Aleksandra M. Walczak, Michael M. Desai
doi: https://doi.org/10.1101/2021.05.25.445596
Angela M. Phillips
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
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Katherine R. Lawrence
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
2NSF-Simons Center for Mathematical and Statistical Analysis of Biology, Harvard University, Cambridge MA 02138
3Quantitative Biology Initiative, Harvard University, Cambridge MA 02138
4Department of Physics, Massachusetts Institute of Technology, Cambridge MA 02139
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Alief Moulana
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
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Thomas Dupic
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
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Jeffrey Chang
5Department of Physics, Harvard University, Cambridge, MA 02138
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Milo S. Johnson
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
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Ivana Cvijović
6Department of Applied Physics, Stanford University, Stanford CA 94305
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Thierry Mora
7Laboratoire de physique de l’École normale supérieure, CNRS, PSL University, Sorbonne Université, and Université de Paris, 75005 Paris, France
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Aleksandra M. Walczak
7Laboratoire de physique de l’École normale supérieure, CNRS, PSL University, Sorbonne Université, and Université de Paris, 75005 Paris, France
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Michael M. Desai
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
2NSF-Simons Center for Mathematical and Statistical Analysis of Biology, Harvard University, Cambridge MA 02138
3Quantitative Biology Initiative, Harvard University, Cambridge MA 02138
5Department of Physics, Harvard University, Cambridge, MA 02138
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Abstract

Over the past two decades, several broadly neutralizing antibodies (bnAbs) that confer protection against diverse influenza strains have been isolated1,2. Structural and biochemical characterization of these bnAbs has provided molecular insight into how they bind distinct antigens1. However, our understanding of the evolutionary pathways leading to bnAbs, and thus how best to elicit them, remains limited. Here, we measure equilibrium dissociation constants of combinatorially complete mutational libraries for two naturally isolated influenza bnAbs3–5 (CR-9114, 16 mutations; CR-6261, 11 mutations), reconstructing all possible intermediates back to the unmutated germline sequences. We find that these two libraries exhibit strikingly different patterns of breadth: while many variants of CR-6261 display moderate affinity to diverse antigens, those of CR-9114 display appreciable affinity only in specific, nested combinations. By examining the extensive pairwise and higher-order epistasis between mutations, we find key sites with strong synergistic interactions that are highly similar across antigens for CR-6261 and different for CR-9114. Together, these features of the binding affinity landscapes strongly favor sequential acquisition of affinity to diverse antigens for CR-9114, while the acquisition of breadth to more similar antigens for CR-6261 is less constrained. These results, if generalizable to other bnAbs, may explain the molecular basis for the widespread observation that sequential exposure favors greater breadth6–8, and such mechanistic insight will be essential for predicting and eliciting broadly protective immune responses.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵§ mdesai{at}oeb.harvard.edu

  • https://yodabrowser.netlify.app/yoda_browser/

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 May 25, 2021.
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Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
Angela M. Phillips, Katherine R. Lawrence, Alief Moulana, Thomas Dupic, Jeffrey Chang, Milo S. Johnson, Ivana Cvijović, Thierry Mora, Aleksandra M. Walczak, Michael M. Desai
bioRxiv 2021.05.25.445596; doi: https://doi.org/10.1101/2021.05.25.445596
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Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
Angela M. Phillips, Katherine R. Lawrence, Alief Moulana, Thomas Dupic, Jeffrey Chang, Milo S. Johnson, Ivana Cvijović, Thierry Mora, Aleksandra M. Walczak, Michael M. Desai
bioRxiv 2021.05.25.445596; doi: https://doi.org/10.1101/2021.05.25.445596

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