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

Authors:

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

Details:

EBioMedicine, Volume 63, 2021-01-31

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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.