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 T. 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 J. Salguero; Miles W. 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. 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 T. 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 J. Salguero, Miles W. Carroll^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

139 Citations (Scopus)

110 Downloads (Pure)

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 (5 × 10⁶ pfu) and medium (5 × 10⁴ 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 (5 × 10² 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.

Original language	English
Article number	81
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 - 1 Dec 2021

Bibliographical note

Publisher Copyright:
© 2021, Crown.

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

SDG 3 Good Health and Well-being

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10.1038/s41467-020-20439-y

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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. W. (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 (5 × 106 pfu) and medium (5 × 104 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 (5 × 102 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.",

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 Pullan, \{Steven T.\} 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, \{Francisco J.\} and Carroll, \{Miles W.\}",

note = "Publisher Copyright: {\textcopyright} 2021, Crown.",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-020-20439-y",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

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, ST, 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, FJ & Carroll, MW 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 T.

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, Francisco J.

AU - Carroll, Miles W.

PY - 2021/12/1

Y1 - 2021/12/1

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 (5 × 106 pfu) and medium (5 × 104 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 (5 × 102 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.

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 (5 × 106 pfu) and medium (5 × 104 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 (5 × 102 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.

UR - https://www.scopus.com/pages/publications/85098648842

U2 - 10.1038/s41467-020-20439-y

DO - 10.1038/s41467-020-20439-y

M3 - Article

C2 - 33398055

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

UN SDGs

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