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Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters

Author

Listed:
  • Shufeng Liu

    (Food and Drug Administration)

  • Charles B. Stauft

    (Food and Drug Administration)

  • Prabhuanand Selvaraj

    (Food and Drug Administration)

  • Prabha Chandrasekaran

    (National Institutes of Health)

  • Felice D’Agnillo

    (Food and Drug Administration)

  • Chao-Kai Chou

    (Food and Drug Administration)

  • Wells W. Wu

    (Food and Drug Administration)

  • Christopher Z. Lien

    (Food and Drug Administration)

  • Clement A. Meseda

    (Food and Drug Administration)

  • Cyntia L. Pedro

    (Food and Drug Administration)

  • Matthew F. Starost

    (National Institutes of Health)

  • Jerry P. Weir

    (Food and Drug Administration)

  • Tony T. Wang

    (Food and Drug Administration)

Abstract

Few live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are in pre-clinical or clinical development. We seek to attenuate SARS-CoV-2 (isolate WA1/2020) by removing the polybasic insert within the spike protein and the open reading frames (ORFs) 6–8, and by introducing mutations that abolish non-structural protein 1 (Nsp1)-mediated toxicity. The derived virus (WA1-ΔPRRA-ΔORF6-8-Nsp1K164A/H165A) replicates to 100- to 1000-fold-lower titers than the ancestral virus and induces little lung pathology in both K18-human ACE2 (hACE2) transgenic mice and Syrian hamsters. Immunofluorescence and transcriptomic analyses of infected hamsters confirm that three-pronged genetic modifications attenuate the proinflammatory pathways more than the removal of the polybasic cleavage site alone. Finally, intranasal administration of just 100 PFU of the WA1-ΔPRRA-ΔORF6-8-Nsp1K164A/H165A elicits robust antibody responses in Syrian hamsters and protects against SARS-CoV-2-induced weight loss and pneumonia. As a proof-of-concept study, we demonstrate that live but sufficiently attenuated SARS-CoV-2 vaccines may be attainable by rational design.

Suggested Citation

  • Shufeng Liu & Charles B. Stauft & Prabhuanand Selvaraj & Prabha Chandrasekaran & Felice D’Agnillo & Chao-Kai Chou & Wells W. Wu & Christopher Z. Lien & Clement A. Meseda & Cyntia L. Pedro & Matthew F., 2022. "Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34571-4
    DOI: 10.1038/s41467-022-34571-4
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    1. Charles B. Stauft & Prabhuanand Selvaraj & Felice D’Agnillo & Clement A. Meseda & Shufeng Liu & Cyntia L. Pedro & Kotou Sangare & Christopher Z. Lien & Jerry P. Weir & Matthew F. Starost & Tony T. Wan, 2023. "Intranasal or airborne transmission-mediated delivery of an attenuated SARS-CoV-2 protects Syrian hamsters against new variants," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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