Computationally designed proteins mimic antibody immune evasion in viral evolution

Copyright and License

© 2025 The Authors. Published by Elsevier Inc. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acknowledgement

The authors would like to thank Stephen Walsh and Lindsey Baden at Brigham and Women's Hospital (Boston, MA) for assisting in the collection of serum from vaccinated individuals for this study, Chris Sander, Andrew Hebbeler, and members of the Luban, Lemieux, Seaman and Marks labs for discussions. We thank Drs. Michael Farzan and Huihui Ma at The Scripps Research Institute for providing the HEK 293T/ACE2 cell line and Dr. Barney Graham at the NIH Vaccine Research Center for providing the pCMV-R8.2 and pHR’CMV-Luc plasmids. The cartoon diagrams in Figures 1A and 2C and the graphical abstract were created in part with Biorender.com. The authors gratefully acknowledge the POSITIVES study team for providing access to serum samples. This work was supported by grants from the Coalition for Epidemic Preparedness Innovations (CEPI) and the Massachusetts Consortium on Pathogen Readiness (MassCPR). J.L. was also supported by an NIH grant (R37 AI147868). We gratefully acknowledge all data contributors, i.e., the authors and their originating laboratories responsible for obtaining the specimens and their submitting laboratories for generating the genetic sequence and metadata and sharing via the GISAID Initiative, on which some of this research is based.

Data Availability

All data are available in the main text or the supplementary materials. All code used for analysis in this study is publicly available on GitHub (https://github.com/debbiemarkslab/Vax_design). Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Conflict of Interest

D.S.M. is an advisor for Dyno Therapeutics, Octant, Jura Bio, Tectonic Therapeutic, and Genentech and is a cofounder of Seismic Therapeutic.

Supplemental Material

• Document S1. Figures S1–S5.

• Table S1. Mutation model summary, related to Figure 1. (A) List of mutations in designed constructs and prevalence in the pandemic.
  (B) Description of the number of sequences used for model training and number of mutations evaluated for the design algorithm.
  (C) Emergence dates used for Variants of Concern.

• Table S2. Construct summary, related to Figure 1. Description of mutations, DNA sequences, and Addgene ID for all designed constructs and natural variants.

• Table S3. Infectivity data, related to Figure 2.

• Table S4. Neutralization data, related to Figures 2, 3, and 4. 
  (A) Number of individual sera samples and pools.
  (B) Neutralization ID₅₀ titers for human sera.
  (C) Neutralization ID₅₀ titers for human sera non-human primate sera.

• Table S5. Summary of experimental studies, related to Figure 5. Description of experimental deep mutational scanning studies.
  
  
• Document S2. Article plus supplemental information.