Computationally designed proteins mimic antibody immune evasion in viral evolution

Noor Youssef¹, Sarah Gurev², Fadi Ghantous³, Kelly P Brock¹, Javier A Jaimes⁴, Nicole N Thadani¹, Ann Dauphin⁴, Amy C Sherman⁵, Leonid Yurkovetskiy⁴, Daria Soto⁴, Ralph Estanboulieh⁶, Ben Kotzen⁷, Pascal Notin¹, Aaron W Kollasch¹, Alexander A Cohen⁸, Sandra E Dross⁹, Jesse Erasmus¹⁰, Deborah H Fuller⁹, Pamela J Bjorkman⁸, Jacob E Lemieux¹¹, Jeremy Luban¹², Michael S Seaman¹³, Debora S Marks¹⁴

Affiliations

¹ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
² Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA.
³ Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
⁴ Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
⁵ Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁶ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Massachusetts General Hospital, Boston, MA 02114, USA.
⁸ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁹ Department of Microbiology, University of Washington, Seattle, WA 98195, USA; National Primate Research Center, Seattle, WA 98109, USA.
¹⁰ HDT Bio, Seattle, WA 98109, USA.
¹¹ Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Massachusetts General Hospital, Boston, MA 02114, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115, USA. Electronic address: lemieux@broadinstitute.org.
¹² Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address: jeremy.luban@umassmed.edu.
¹³ Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Electronic address: mseaman@bidmc.harvard.edu.
¹⁴ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Electronic address: debbie@hms.harvard.edu.

PMID: 40345199
DOI: 10.1016/j.immuni.2025.04.015

Free article

Computationally designed proteins mimic antibody immune evasion in viral evolution

Noor Youssef et al. Immunity. 2025.

Free article

. 2025 Jun 10;58(6):1411-1421.e6.

doi: 10.1016/j.immuni.2025.04.015. Epub 2025 May 8.

Authors

Affiliations

¹ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
² Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA.
³ Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
⁴ Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
⁵ Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁶ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Massachusetts General Hospital, Boston, MA 02114, USA.
⁸ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁹ Department of Microbiology, University of Washington, Seattle, WA 98195, USA; National Primate Research Center, Seattle, WA 98109, USA.
¹⁰ HDT Bio, Seattle, WA 98109, USA.
¹¹ Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Massachusetts General Hospital, Boston, MA 02114, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115, USA. Electronic address: lemieux@broadinstitute.org.
¹² Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address: jeremy.luban@umassmed.edu.
¹³ Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Electronic address: mseaman@bidmc.harvard.edu.
¹⁴ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Electronic address: debbie@hms.harvard.edu.

PMID: 40345199
DOI: 10.1016/j.immuni.2025.04.015

Abstract

Recurrent waves of viral infection necessitate vaccines and therapeutics that remain effective against emerging viruses. Our ability to evaluate interventions is currently limited to assessments against past or circulating variants, which likely differ in their immune escape potential compared with future variants. To address this, we developed EVE-Vax, a computational method for designing antigens that foreshadow immune escape observed in future viral variants. We designed 83 SARS-CoV-2 spike proteins that transduced ACE2-positive cells and displayed neutralization resistance comparable to variants that emerged up to 12 months later in the COVID-19 pandemic. Designed spikes foretold antibody escape from B.1-BA.4/5 bivalent booster sera seen in later variants. The designed constructs also highlighted the increased neutralization breadth elicited by nanoparticle-based, compared with mRNA-based, boosters in non-human primates. Our approach offers targeted panels of synthetic proteins that map the immune landscape for early vaccine and therapeutic evaluation against future viral strains.

Keywords: antibody escape; generative protein models; immune landscape; machine learning; protein design; vaccine evaluation; viral evolution.

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Conflict of interest statement

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

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Computationally designed proteins mimic antibody immune evasion in viral evolution

Affiliations

Computationally designed proteins mimic antibody immune evasion in viral evolution

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous