Computationally designed proteins mimic antibody immune evasion in viral evolution.

Journal: Immunity
Published Date: May 6, 2025

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.

Authors

  • Noor Youssef
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
  • Sarah Gurev
    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.
  • Fadi Ghantous
    Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
  • Kelly P Brock
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
  • Javier A Jaimes
    Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
  • Nicole N Thadani
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
  • Ann Dauphin
    Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
  • Amy C Sherman
    Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Leonid Yurkovetskiy
    Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
  • Daria Soto
    Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
  • Ralph Estanboulieh
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Ben Kotzen
    Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Massachusetts General Hospital, Boston, MA 02114, USA.
  • Pascal Notin
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
  • Aaron W Kollasch
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
  • Alexander A Cohen
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  • Sandra E Dross
    Department of Microbiology, University of Washington, Seattle, WA 98195, USA; National Primate Research Center, Seattle, WA 98109, USA.
  • Jesse Erasmus
    HDT Bio, Seattle, WA 98109, USA.
  • Deborah H Fuller
    Department of Microbiology, University of Washington, Seattle, WA 98195, USA; National Primate Research Center, Seattle, WA 98109, USA.
  • Pamela J Bjorkman
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  • Jacob E Lemieux
    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.
  • Jeremy Luban
    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.
  • Michael S Seaman
    Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Electronic address: mseaman@bidmc.harvard.edu.
  • Debora S Marks
    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.

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