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Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity

Author

Listed:
  • Wei-Hung Chen

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Agnes Hajduczki

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Elizabeth J. Martinez

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Hongjun Bai

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • Hanover Matz

    (University of Maryland School of Medicine
    Institute of Marine and Environmental Technology)

  • Thomas M. Hill

    (University of Maryland School of Medicine
    Institute of Marine and Environmental Technology)

  • Eric Lewitus

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • William C. Chang

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Layla Dawit

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Caroline E. Peterson

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Phyllis A. Rees

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Adelola B. Ajayi

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Emily S. Golub

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Isabella Swafford

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • Vincent Dussupt

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • Sapna David

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Sandra V. Mayer

    (Henry M. Jackson Foundation for the Advancement of Military Medicine
    Viral Diseases Branch, Walter Reed Army Institute of Research)

  • Sandrine Soman

    (Viral Diseases Branch, Walter Reed Army Institute of Research)

  • Caitlin Kuklis

    (Viral Diseases Branch, Walter Reed Army Institute of Research)

  • Courtney Corbitt

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    Viral Diseases Branch, Walter Reed Army Institute of Research)

  • Jocelyn King

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    Viral Diseases Branch, Walter Reed Army Institute of Research)

  • Misook Choe

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Rajeshwer S. Sankhala

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Paul V. Thomas

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

  • Michelle Zemil

    (U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • Lindsay Wieczorek

    (Henry M. Jackson Foundation for the Advancement of Military Medicine
    U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • Tricia Hart

    (Trudeau Institute)

  • Debora Duso

    (Trudeau Institute)

  • Larry Kummer

    (Trudeau Institute)

  • Lianying Yan

    (Uniformed Services University)

  • Spencer L. Sterling

    (Uniformed Services University)

  • Eric D. Laing

    (Uniformed Services University)

  • Christopher C. Broder

    (Uniformed Services University)

  • Jazmean K. Williams

    (Integral Molecular)

  • Edgar Davidson

    (Integral Molecular)

  • Benjamin J. Doranz

    (Integral Molecular)

  • Shelly J. Krebs

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • Victoria R. Polonis

    (U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • Dominic Paquin-Proulx

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • Morgane Rolland

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine
    U.S. Military HIV Research Program, Walter Reed Army Institute of Research)

  • William W. Reiley

    (Trudeau Institute)

  • Gregory D. Gromowski

    (Viral Diseases Branch, Walter Reed Army Institute of Research)

  • Kayvon Modjarrad

    (Walter Reed Army Institute of Research)

  • Helen Dooley

    (University of Maryland School of Medicine
    Institute of Marine and Environmental Technology)

  • M. Gordon Joyce

    (Walter Reed Army Institute of Research
    Henry M. Jackson Foundation for the Advancement of Military Medicine)

Abstract

Despite rapid and ongoing vaccine and therapeutic development, SARS-CoV-2 continues to evolve and evade, presenting a need for next-generation diverse therapeutic modalities. Here we show that nurse sharks immunized with SARS-CoV-2 recombinant receptor binding domain (RBD), RBD-ferritin (RFN), or spike protein ferritin nanoparticle (SpFN) immunogens elicit a set of new antigen receptor antibody (IgNAR) molecules that target two non-overlapping conserved epitopes on the spike RBD. Representative shark antibody variable NAR-Fc chimeras (ShAbs) targeting either of the two epitopes mediate cell-effector functions, with high affinity to all SARS-CoV-2 viral variants of concern, including the divergent Omicron strains. The ShAbs potently cross-neutralize SARS-CoV-2 WA-1, Alpha, Beta, Delta, Omicron BA.1 and BA.5, and SARS-CoV-1 pseudoviruses, and confer protection against SARS-CoV-2 challenge in the K18-hACE2 transgenic mouse model. Structural definition of the RBD-ShAb01-ShAb02 complex enabled design and production of multi-specific nanobodies with enhanced neutralization capacity, and picomolar affinity to divergent sarbecovirus clade 1a, 1b and 2 RBD molecules. These shark nanobodies represent potent immunotherapeutics both for current use, and future sarbecovirus pandemic preparation.

Suggested Citation

  • Wei-Hung Chen & Agnes Hajduczki & Elizabeth J. Martinez & Hongjun Bai & Hanover Matz & Thomas M. Hill & Eric Lewitus & William C. Chang & Layla Dawit & Caroline E. Peterson & Phyllis A. Rees & Adelola, 2023. "Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36106-x
    DOI: 10.1038/s41467-023-36106-x
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    References listed on IDEAS

    as
    1. Obinna C. Ubah & Eric W. Lake & Gihan S. Gunaratne & Joseph P. Gallant & Marie Fernie & Austin J. Robertson & Jonathan S. Marchant & Tyler D. Bold & Ryan A. Langlois & William E. Matchett & Joshua M. , 2021. "Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Christopher O. Barnes & Claudia A. Jette & Morgan E. Abernathy & Kim-Marie A. Dam & Shannon R. Esswein & Harry B. Gristick & Andrey G. Malyutin & Naima G. Sharaf & Kathryn E. Huey-Tubman & Yu E. Lee &, 2020. "SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies," Nature, Nature, vol. 588(7839), pages 682-687, December.
    3. Jianliang Xu & Kai Xu & Seolkyoung Jung & Andrea Conte & Jenna Lieberman & Frauke Muecksch & Julio Cesar Cetrulo Lorenzi & Solji Park & Fabian Schmidt & Zijun Wang & Yaoxing Huang & Yang Luo & Manoj S, 2021. "Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants," Nature, Nature, vol. 595(7866), pages 278-282, July.
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    1. Rajeshwer S. Sankhala & Kerri G. Lal & Jaime L. Jensen & Vincent Dussupt & Letzibeth Mendez-Rivera & Hongjun Bai & Lindsay Wieczorek & Sandra V. Mayer & Michelle Zemil & Danielle A. Wagner & Samantha , 2024. "Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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