Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model

Pamela C. Proud, Daphne Tsitoura, Robert J. Watson, Brendon Y. Chua, Marilyn J. Aram, Kevin R. Bewley, Breeze E. Cavell, Rebecca Cobb, Stuart Dowall, Susan A. Fotheringham, Catherine M.K. Ho, Vanessa Lucas, Didier Ngabo, Emma Rayner, Kathryn A. Ryan, Gillian S. Slack, Stephen Thomas, Nadina I. Wand, Paul Yeates, Christophe DemaisonWeiguang Zeng, Ian Holmes, David C. Jackson, Nathan W. Bartlett, Francesca Mercuri, Miles Carroll

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

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: 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 × 106 pfu/ml. Treatment groups received intranasal INNA-051, developed by Ena Respiratory. SARS-CoV-2 RNA was detected using the 2019-nCoV CDC RUO Kit and QuantStudio™ 7 Flex Real-Time PCR System. Histopathological analysis was performed using cut tissues stained with haematoxylin and eosin (H&E). Findings: 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: 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: This work was funded by Ena Respiratory, Melbourne, Australia.

Original languageEnglish
Article number103153
JournalEBioMedicine
Volume63
DOIs
Publication statusPublished - Jan 2021

Keywords

  • COVID-19
  • Ferret
  • INNA-051
  • SARS-CoV-2
  • TLR-2
  • Viral shedding

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