Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model.
Administration, Intranasal
Animals
COVID-19
/ pathology
Disease Models, Animal
Female
Ferrets
Immunity, Innate
Lipopeptides
/ administration & dosage
Nasal Cavity
/ pathology
Pharynx
/ pathology
RNA, Viral
/ metabolism
Real-Time Polymerase Chain Reaction
Respiratory System
/ pathology
SARS-CoV-2
/ genetics
Toll-Like Receptor 2
/ agonists
Toll-Like Receptor 6
/ agonists
Viral Load
/ drug effects
Virus Shedding
COVID-19 Drug Treatment
COVID-19
Ferret
INNA-051
SARS-CoV-2
TLR-2
Viral shedding
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
received:
24
08
2020
revised:
16
10
2020
accepted:
13
11
2020
pubmed:
7
12
2020
medline:
29
1
2021
entrez:
6
12
2020
Statut:
ppublish
Résumé
The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 10 We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=<0.0001) by up to a 24 fold (96% reduction) and in nasal wash (p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals. The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19. This work was funded by Ena Respiratory, Melbourne, Australia.
Sections du résumé
BACKGROUND
BACKGROUND
The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission.
METHODS
METHODS
SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 10
FINDINGS
RESULTS
We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=<0.0001) by up to a 24 fold (96% reduction) and in nasal wash (p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals.
INTERPRETATION
CONCLUSIONS
The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19.
FUNDING
BACKGROUND
This work was funded by Ena Respiratory, Melbourne, Australia.
Identifiants
pubmed: 33279857
pii: S2352-3964(20)30529-6
doi: 10.1016/j.ebiom.2020.103153
pmc: PMC7711201
pii:
doi:
Substances chimiques
Lipopeptides
0
RNA, Viral
0
Toll-Like Receptor 2
0
Toll-Like Receptor 6
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103153Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interests Authors report grants from Ena Respiratory, during the conduct of the study. W. Zeng and D.C. Jackson reports grants from Ena Therapeutics, during the conduct of the study. D. Tsitoura, C. Demaison, F. Mercuri, I. Holmes and N.W. Bartlett reports personal fees and other from Ena Therapeutics, outside the submitted work. D.C. Jackson, W. Zeng and B.Y. Chua reports other from Ena Therapeutics, outside the submitted work. Dr. Holmes reports personal fees from Ena Therapeutics, outside the submitted work. In addition, D. Tsitoura, C. Demaison and F. Mercuri have a patent AU 2020901709 pending to Ena Therapeutics. D.C Jackson, W. Zeng and C. Demaison have a patent PCT/AU2011/001225 issued to Ena Therapeutics. D.C Jackson, W. Zeng, I. Holmes and C. Demaison have a patent PCT/AU2020/050660 pending to Ena Therapeutics.
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