Design and validation of an exposure system for efficient inter-animal SARS-CoV-2 airborne transmission in Syrian hamsters.

IMPORTANCE: The main route of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is airborne. However, there are few experimental systems that can assess the airborne transmission dynamics of SARS-CoV-2 in vivo. Here, we designed, built, and characterized a hamster transmission caging and exposure system that allows for efficient SARS-CoV-2 airborne transmission in Syrian hamsters without contributions from fomite or direct contact transmission. We successfully measured SARS-CoV-2 viral RNA in aerosols and demonstrated that SARS-CoV-2 is transmitted efficiently at either a 1:1 or 1:4 infected index to naïve recipient hamster ratio. This is meaningful as a 1:4 infected index to naïve hamster ratio would allow for simultaneous comparisons of various interventions in naïve animals to determine their susceptibility to infection by aerosol transmission of SARS-CoV-2. Our SARS-CoV-2 exposure system allows for testing viral airborne transmission dynamics and transmission-blocking therapeutic strategies against SARS-CoV-2 in Syrian hamsters.

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys.

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5'-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3-7-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved presystemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP, leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350-400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2, which supports development of 3 as a promising COVID-19 treatment.

Animal Models for the Study of SARS-CoV-2-Induced Respiratory Disease and Pathology.

Emergence of the betacoronavirus SARS-CoV-2 has resulted in a historic pandemic, with millions of deaths worldwide. An unprecedented effort has been made by the medical, scientific, and public health communities to rapidly develop and implement vaccines and therapeutics to prevent and reduce hospitalizations and deaths. Although SARS-CoV-2 infection can lead to disease in many organ systems, the respiratory system is its main target, with pneumonia and acute respiratory distress syndrome as the hallmark features of severe disease. The large number of patients who have contracted COVID-19 infections since 2019 has permitted a detailed characterization of the clinical and pathologic features of the disease in humans. However, continued progress in the development of effective preventatives and therapies requires a deeper understanding of the pathogenesis of infection. Studies using animal models are necessary to complement in vitro findings and human clinical data. Multiple animal species have been evaluated as potential models for studying the respiratory disease caused by SARSCoV-2 infection. Knowing the similarities and differences between animal and human responses to infection is critical for effective translation of animal data into human medicine. This review provides a detailed summary of the respiratory disease and associated pathology induced by SARS-CoV-2 infection in humans and compares them with the disease that develops in 3 commonly used models: NHP, hamsters, and mice. The effective use of animals to study SARS-CoV-2-induced respiratory disease will enhance our understanding of SARS-CoV-2 pathogenesis, allow the development of novel preventatives and therapeutics, and aid in the preparation for the next emerging virus with pandemic potential.

Animal Models of Enterovirus D68 Infection and Disease.

Human enterovirus D68 (EV-D68) is a globally reemerging respiratory pathogen that is associated with the development of acute flaccid myelitis (AFM) in children. Currently, there are no approved vaccines or treatments for EV-D68 infection, and there is a paucity of data related to the virus and host-specific factors that predict disease severity and progression to the neurologic syndrome. EV-D68 infection of various animal models has served as an important platform for characterization and comparison of disease pathogenesis between historic and contemporary isolates. Still, there are significant gaps in our knowledge of EV-D68 pathogenesis that constrain the development and evaluation of targeted vaccines and antiviral therapies. Continued refinement and characterization of animal models that faithfully reproduce key elements of EV-D68 infection and disease is essential for ensuring public health preparedness for future EV-D68 outbreaks.