Characterization of Three Variants of SARS-CoV-2 in vivo Shows Host-Dependent Pathogenicity in Hamsters

Toomer, G.; Burns, W.; Melendez, M.; Garcia, L.; Henry, G.; Biancofiori, A.; Geroge, A.; Duffy, C.; Chu, J.; Sides, M.; Munoz, M.; Garcia, K.; Nikolai-Yogerst, A.; Peng, X.; Westfall, L.; Baker, R. O.

doi:10.1101/2022.10.24.513632

bioRxiv · 10.1101/2022.10.24.513632

Characterization of Three Variants of SARS-CoV-2 in vivo Shows Host-Dependent Pathogenicity in Hamsters

Toomer, G.·Burns, W.·Melendez, M.·Garcia, L.·Henry, G.·Biancofiori, A.·Geroge, A.·Duffy, C.·Chu, J.·Sides, M.·Munoz, M.·Garcia, K.·Nikolai-Yogerst, A.·Peng, X.·Westfall, L.·Baker, R. O.

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Abstract

Animal models are used in preclinical trials to test vaccines, antivirals, monoclonal antibodies, and immunomodulatory drug therapies against SARS-CoV-2. However, these drugs often do not produce equivalent results in human clinical trials. Here, we show how different animal models infected with some of the most clinically relevant SARS-CoV-2 variants, WA1/2020, B.1.617.2/Delta, B.1.1.529/Omicron and BA5.2/Omicron, have independent outcomes. We show that in mice, B.1.617.2 is more pathogenic, followed by WA1, while B.1.1.529 showed an absence of clinical signs. Only B.1.1.529 was able to infect C57BL/6J mice, which lack the human ACE2 receptor. B.1.1.529-infected ACE2 mice had different T cell profiles compared to infected K18-hACE2 mice, while viral shedding profiles and viral titers in lungs were similar between the ACE2 and the C57BL/6J mice. These data suggest B.1.1.529 virus adaptation to a new host and shows that asymptomatic carriers can accumulate and shed virus. Next, we show how B.1.617.2, WA1 and BA5.2/Omicron have similar viral replication kinetics, pathogenicity, and viral shedding profiles in hamsters, demonstrating that the increased pathogenicity of B.1.617.2 observed in mice is host-dependent. Overall, these findings suggest that small animal models are useful to parallel human clinical data, but the experimental design places an important role in interpreting the data. IMPORTANCEThere is a need to investigate SARS-CoV-2 variants phenotypes in different animal models due to the lack of reproducible outcomes when translating experiments to the human population. Our findings highlight the correlation of clinically relevant SARS-CoV-2 variants in animal models with human infections. Experimental design and understanding of correct animal models are essential to interpreting data to develop antivirals, vaccines, and other therapeutic compounds against COVID-19.

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Toomer, G., Burns, W., Melendez, M., Garcia, L., Henry, G., Biancofiori, A., Geroge, A., Duffy, C., Chu, J., Sides, M., Munoz, M., Garcia, K., Nikolai-Yogerst, A., Peng, X., Westfall, L., Baker, R. O.. 2022-10-26. Characterization of Three Variants of SARS-CoV-2 in vivo Shows Host-Dependent Pathogenicity in Hamsters. https://doi.org/10.1101/2022.10.24.513632

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