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

SARS-CoV-2 is a highly transmissible respiratory pathogen whose main transmission route is airborne. Development of an animal model and exposure system that recapitulates airborne transmission of SARS-CoV-2 is integral for understanding the dynamics of SARS-CoV-2 spread in individuals and populations. Here we designed, built, and characterized a hamster transmission caging and exposure system that allows for efficient SARS-CoV-2 airborne transmission from an infected index animal to naive recipients under unidirectional airflow, without contribution from fomite or direct contact transmission. To validate our system, we assessed a 1:1 or 1:4 ratio of infected index to naive recipient hamsters and compared their virological and clinical measurements after eight hours of airborne exposure. Airborne exposure concentrations and pulmonary deposited dose of SARS-CoV-2 in index and naive hamsters, respectively, were similar in both groups. Daily nasal viral RNA levels, and terminal (day 5) lung viral RNA and infectious virus, and fecal viral RNA levels were statistically similar among 1:1 and 1:4 naive animals. However, virological measurements in the 1:4 naive animals were more variable than the 1:1 naive animals, likely due to hamster piling behavior creating uneven SARS-CoV-2 exposure during the grouped 1:4 airborne exposure. This resulted in slight, but not statistically significant, changes in daily body weights between the 1:1 and 1:4 naive groups. Our report describes a multi-chamber caging and exposure system that allowed for efficient SARS-CoV-2 airborne transmission in single and grouped hamsters. This system can be used to better define airborne transmission dynamics and test transmission-blocking therapeutic strategies against SARS-CoV-2. ImportanceThe main route of SARS-CoV-2 transmission is airborne. However, there are few experimental systems that can assess 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 naive recipient hamster ratio. This is meaningful as a 1:4 infected index to naive hamster ratio would allow for simultaneous comparisons of various interventions in naive animals to determine their susceptibility of 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.

AUG-3387, a Human-Derived Monoclonal Antibody Neutralizes SARS-CoV-2 Variants and Reduces Viral Load from Therapeutic Treatment of Hamsters In Vivo

Infections from the SARS-CoV-2 virus have killed over 4.6 million people since it began spreading through human populations in late 2019. In order to develop a therapeutic or prophylactic antibody to help mitigate the effects of the pandemic, a human monoclonal antibody (mAb) that binds to the SARS-CoV-2 spike protein was isolated from a convalescent patient following recovery from COVID-19 disease. This mAb, designated AUG-3387, demonstrates a high affinity for the spike protein of the original viral strains and all variants tested to date. In vitro pseudovirus neutralization and SARS-CoV-2 neutralization activity has been demonstrated in vitro. In addition, a dry powder formulation has been prepared using a Thin-Film Freezing (TFF) process that exhibited a fine particle fraction (FPF) of 50.95 {+/-} 7.69% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 3.74 {+/-} 0.73 {micro}m and 2.73 {+/-} 0.20, respectively. The dry powder is suitable for delivery directly to the lungs of infected patients using a dry powder inhaler device. Importantly, AUG-3387, administered as a liquid by intraperitoneal injection or the dry powder formulation delivered intratracheally into Syrian hamsters 24 hours after intranasal SARS-CoV-2 infection, demonstrated a dose-dependent reduction in the lung viral load of the virus. These data suggest that AUG-3387 formulated as a dry powder demonstrates potential to treat COVID-19.

Oral and intranasal Ad5 SARS-CoV-2 vaccines decrease disease and viral transmission in a golden hamster model

Transmission-blocking strategies that slow the spread of SARS-CoV-2 and protect against COVID-19 are needed. We have developed a shelf-stable, orally-delivered Ad5-vectored SARS-CoV-2 vaccine candidate that expresses the spike protein. Here we demonstrated that oral and intranasal SARS-CoV-2 vaccination of this candidate protected against disease in index hamsters, and decreased aerosol transmission to unvaccinated, naive hamsters. We confirmed that mucosally-vaccinated hamsters had robust antibody responses. We then induced a post-vaccination infection by inoculating vaccinated index hamsters with SARS-CoV-2. Oral and IN-vaccinated hamsters had decreased viral RNA and infectious virus in the nose and lungs and experienced less lung pathology compared to mock-vaccinated hamsters post challenge. Naive hamsters exposed in a unidirectional air flow chamber to mucosally-vaccinated, SARS-CoV-2-infected hamsters had lower nasal swab viral RNA and exhibited less clinical symptoms of disease than control animals. Our data demonstrate that oral immunization is a viable strategy to decrease SARS-CoV-2 disease and aerosol transmission.