Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity

Kathryn A. Ryan; Kevin R. Bewley; Susan A. Fotheringham; Gillian S. Slack; Phillip Brown; Yper Hall; Nadina I. Wand; Anthony C. Marriott; Breeze E. Cavell; Julia A. Tree; Lauren Allen; Marilyn J. Aram; Thomas J. Bean; Emily Brunt; Karen R. Buttigieg; Daniel P. Carter; Rebecca Cobb; Naomi S. Coombes; Steve J. Findlay-Wilson; Kerry J. Godwin; Karen E. Gooch; Jade Gouriet; Rachel Halkerston; Debbie J. Harris; Thomas H. Hender; Holly E. Humphries; Laura Hunter; Catherine M.K. Ho; Chelsea L. Kennard; Stephanie Leung; Stephanie Longet; Didier Ngabo; Karen L. Osman; Jemma Paterson; Elizabeth J. Penn; Steven Pullan; Emma Rayner; Oliver Skinner; Kimberley Steeds; Irene Taylor; Tom Tipton; Stephen Thomas; Carrie Turner; Robert J. Watson; Nathan R. Wiblin; Sue Charlton; Bassam Hallis; Julian A. Hiscox; Simon Funnell; Mike J. Dennis; Catherine J. Whittaker; Michael G. Catton; Julian Druce; Francisco Javier Salguero Bodes; Miles Carroll

doi:10.1038/s41467-020-20439-y

Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity

Kathryn A. Ryan, Kevin R. Bewley, Susan A. Fotheringham, Gillian S. Slack, Phillip Brown, Yper Hall, Nadina I. Wand, Anthony C. Marriott, Breeze E. Cavell, Julia A. Tree, Lauren Allen, Marilyn J. Aram, Thomas J. Bean, Emily Brunt, Karen R. Buttigieg, Daniel P. Carter, Rebecca Cobb, Naomi S. Coombes, Steve J. Findlay-Wilson, Kerry J. GodwinKaren E. Gooch, Jade Gouriet, Rachel Halkerston, Debbie J. Harris, Thomas H. Hender, Holly E. Humphries, Laura Hunter, Catherine M.K. Ho, Chelsea L. Kennard, Stephanie Leung, Stephanie Longet, Didier Ngabo, Karen L. Osman, Jemma Paterson, Elizabeth J. Penn, Steven Pullan, Emma Rayner, Oliver Skinner, Kimberley Steeds, Irene Taylor, Tom Tipton, Stephen Thomas, Carrie Turner, Robert J. Watson, Nathan R. Wiblin, Sue Charlton, Bassam Hallis, Julian A. Hiscox, Simon Funnell, Mike J. Dennis, Catherine J. Whittaker, Michael G. Catton, Julian Druce, Francisco Javier Salguero Bodes, Miles Carroll^*

^*Corresponding author for this work

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Abstract

There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5x10(6)pfu) and medium (5x10(4)pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5x10(2)pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease. SARS-CoV-2 induces mild infection in ferret model. Here, Ryan et al. characterise optimal infection dosage inducing upper respiratory tract (UTR) viral shedding, progression time of viral shedding, and pathology in ferrets and finally provide evidence for protection after re-challenge.

Original language	English
Article number	81
Number of pages	13
Journal	Nature Communications
Volume	12
Issue number	1
Early online date	4 Jan 2021
DOIs	https://doi.org/10.1038/s41467-020-20439-y
Publication status	Published - 4 Jan 2021

Bibliographical note

Funding Information:
The authors gratefully acknowledge the support from the Biological Investigations Group at the National Infection Service, PHE, Porton Down, UK. The views expressed in this paper are those of the authors and not necessarily those of the funding body. This work was funded by the US Food and Drug Administration [Contract number: HHSF223201710194C].

Open Access: This article is licensed under a Creative Commons Attribution
4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Publisher Copyright: © Crown 2021

Citation: Ryan, K.A., Bewley, K.R., Fotheringham, S.A. et al. Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity. Nat Commun 12, 81 (2021).

DOI: https://doi.org/10.1038/s41467-020-20439-y

Keywords

ACUTE RESPIRATORY SYNDROME
INFLUENZA-VIRUS PATHOGENESIS
SARS CORONAVIRUS INFECTION
ANIMAL-MODELS
TRANSMISSION
VACCINE
CATS
MICE

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Ryan2021Dose-DependentResponseToInfectionWithSARS-CoV-2NatCommunFinal published version, 3.06 MBLicence: CC BY

Cite this

Ryan, K. A., Bewley, K. R., Fotheringham, S. A., Slack, G. S., Brown, P., Hall, Y., Wand, N. I., Marriott, A. C., Cavell, B. E., Tree, J. A., Allen, L., Aram, M. J., Bean, T. J., Brunt, E., Buttigieg, K. R., Carter, D. P., Cobb, R., Coombes, N. S., Findlay-Wilson, S. J., ... Carroll, M. (2021). Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity. Nature Communications, 12(1), Article 81. https://doi.org/10.1038/s41467-020-20439-y

@article{39e969494a5545c4816902421991eba4,

title = "Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity",

abstract = "There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5x10(6)pfu) and medium (5x10(4)pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5x10(2)pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease. SARS-CoV-2 induces mild infection in ferret model. Here, Ryan et al. characterise optimal infection dosage inducing upper respiratory tract (UTR) viral shedding, progression time of viral shedding, and pathology in ferrets and finally provide evidence for protection after re-challenge.",

keywords = "ACUTE RESPIRATORY SYNDROME, INFLUENZA-VIRUS PATHOGENESIS, SARS CORONAVIRUS INFECTION, ANIMAL-MODELS, TRANSMISSION, VACCINE, CATS, MICE",

author = "Ryan, {Kathryn A.} and Bewley, {Kevin R.} and Fotheringham, {Susan A.} and Slack, {Gillian S.} and Phillip Brown and Yper Hall and Wand, {Nadina I.} and Marriott, {Anthony C.} and Cavell, {Breeze E.} and Tree, {Julia A.} and Lauren Allen and Aram, {Marilyn J.} and Bean, {Thomas J.} and Emily Brunt and Buttigieg, {Karen R.} and Carter, {Daniel P.} and Rebecca Cobb and Coombes, {Naomi S.} and Findlay-Wilson, {Steve J.} and Godwin, {Kerry J.} and Gooch, {Karen E.} and Jade Gouriet and Rachel Halkerston and Harris, {Debbie J.} and Hender, {Thomas H.} and Humphries, {Holly E.} and Laura Hunter and Ho, {Catherine M.K.} and Kennard, {Chelsea L.} and Stephanie Leung and Stephanie Longet and Didier Ngabo and Osman, {Karen L.} and Jemma Paterson and Penn, {Elizabeth J.} and Steven Pullan and Emma Rayner and Oliver Skinner and Kimberley Steeds and Irene Taylor and Tom Tipton and Stephen Thomas and Carrie Turner and Watson, {Robert J.} and Wiblin, {Nathan R.} and Sue Charlton and Bassam Hallis and Hiscox, {Julian A.} and Simon Funnell and Dennis, {Mike J.} and Whittaker, {Catherine J.} and Catton, {Michael G.} and Julian Druce and {Salguero Bodes}, {Francisco Javier} and Miles Carroll",

note = "Funding Information: The authors gratefully acknowledge the support from the Biological Investigations Group at the National Infection Service, PHE, Porton Down, UK. The views expressed in this paper are those of the authors and not necessarily those of the funding body. This work was funded by the US Food and Drug Administration [Contract number: HHSF223201710194C]. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Publisher Copyright: {\textcopyright} Crown 2021 Citation: Ryan, K.A., Bewley, K.R., Fotheringham, S.A. et al. Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity. Nat Commun 12, 81 (2021). DOI: https://doi.org/10.1038/s41467-020-20439-y",

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Ryan, KA , Bewley, KR , Fotheringham, SA, Slack, GS, Brown, P , Hall, Y, Wand, NI, Marriott, AC , Cavell, BE , Tree, JA , Allen, L, Aram, MJ, Bean, TJ, Brunt, E, Buttigieg, KR , Carter, DP, Cobb, R, Coombes, NS , Findlay-Wilson, SJ , Godwin, KJ , Gooch, KE, Gouriet, J, Halkerston, R, Harris, DJ, Hender, TH, Humphries, HE , Hunter, L, Ho, CMK, Kennard, CL, Leung, S, Longet, S, Ngabo, D, Osman, KL, Paterson, J, Penn, EJ, Pullan, S, Rayner, E, Skinner, O, Steeds, K, Taylor, I, Tipton, T, Thomas, S , Turner, C, Watson, RJ, Wiblin, NR, Charlton, S , Hallis, B, Hiscox, JA, Funnell, S , Dennis, MJ , Whittaker, CJ, Catton, MG, Druce, J, Salguero Bodes, FJ & Carroll, M 2021, 'Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity', Nature Communications, vol. 12, no. 1, 81. https://doi.org/10.1038/s41467-020-20439-y

TY - JOUR

T1 - Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity

AU - Ryan, Kathryn A.

AU - Bewley, Kevin R.

AU - Fotheringham, Susan A.

AU - Slack, Gillian S.

AU - Brown, Phillip

AU - Hall, Yper

AU - Wand, Nadina I.

AU - Marriott, Anthony C.

AU - Cavell, Breeze E.

AU - Tree, Julia A.

AU - Allen, Lauren

AU - Aram, Marilyn J.

AU - Bean, Thomas J.

AU - Brunt, Emily

AU - Buttigieg, Karen R.

AU - Carter, Daniel P.

AU - Cobb, Rebecca

AU - Coombes, Naomi S.

AU - Findlay-Wilson, Steve J.

AU - Godwin, Kerry J.

AU - Gooch, Karen E.

AU - Gouriet, Jade

AU - Halkerston, Rachel

AU - Harris, Debbie J.

AU - Hender, Thomas H.

AU - Humphries, Holly E.

AU - Hunter, Laura

AU - Ho, Catherine M.K.

AU - Kennard, Chelsea L.

AU - Leung, Stephanie

AU - Longet, Stephanie

AU - Ngabo, Didier

AU - Osman, Karen L.

AU - Paterson, Jemma

AU - Penn, Elizabeth J.

AU - Pullan, Steven

AU - Rayner, Emma

AU - Skinner, Oliver

AU - Steeds, Kimberley

AU - Taylor, Irene

AU - Tipton, Tom

AU - Thomas, Stephen

AU - Turner, Carrie

AU - Watson, Robert J.

AU - Wiblin, Nathan R.

AU - Charlton, Sue

AU - Hallis, Bassam

AU - Hiscox, Julian A.

AU - Funnell, Simon

AU - Dennis, Mike J.

AU - Whittaker, Catherine J.

AU - Catton, Michael G.

AU - Druce, Julian

AU - Salguero Bodes, Francisco Javier

AU - Carroll, Miles

N1 - Funding Information: The authors gratefully acknowledge the support from the Biological Investigations Group at the National Infection Service, PHE, Porton Down, UK. The views expressed in this paper are those of the authors and not necessarily those of the funding body. This work was funded by the US Food and Drug Administration [Contract number: HHSF223201710194C]. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Publisher Copyright: © Crown 2021 Citation: Ryan, K.A., Bewley, K.R., Fotheringham, S.A. et al. Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity. Nat Commun 12, 81 (2021). DOI: https://doi.org/10.1038/s41467-020-20439-y

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N2 - There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5x10(6)pfu) and medium (5x10(4)pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5x10(2)pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease. SARS-CoV-2 induces mild infection in ferret model. Here, Ryan et al. characterise optimal infection dosage inducing upper respiratory tract (UTR) viral shedding, progression time of viral shedding, and pathology in ferrets and finally provide evidence for protection after re-challenge.

AB - There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5x10(6)pfu) and medium (5x10(4)pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5x10(2)pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease. SARS-CoV-2 induces mild infection in ferret model. Here, Ryan et al. characterise optimal infection dosage inducing upper respiratory tract (UTR) viral shedding, progression time of viral shedding, and pathology in ferrets and finally provide evidence for protection after re-challenge.

KW - ACUTE RESPIRATORY SYNDROME

KW - INFLUENZA-VIRUS PATHOGENESIS

KW - SARS CORONAVIRUS INFECTION

KW - ANIMAL-MODELS

KW - TRANSMISSION

KW - VACCINE

KW - CATS

KW - MICE

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AN - SCOPUS:85098648842

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 81

ER -

Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity

Abstract

Bibliographical note

Keywords

UN SDGs

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