{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T20:26:54Z","timestamp":1761337614993,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>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 K18-hACE2 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 C57BL\/6J 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 K18-hACE2 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. Importance: There is a need to investigate SARS-CoV-2 variant 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.<\/jats:p>","DOI":"10.3390\/v14112584","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T03:04:20Z","timestamp":1669086260000},"page":"2584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Characterization of Three Variants of SARS-CoV-2 In Vivo Shows Host-Dependent Pathogenicity in Hamsters, While Not in K18-hACE2 Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Gabriela","family":"Toomer","sequence":"first","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Whitney","family":"Burns","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liliana","family":"Garcia","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerelyn","family":"Henry","sequence":"additional","affiliation":[{"name":"Department of Pathology, Charles River Laboratories, Inc., Chicago, IL 60077, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Biancofiori","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"George","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciera","family":"Duffy","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan","family":"Sides","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly","family":"Garcia","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anya","family":"Nikolai-Yogerst","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinjian","family":"Peng","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Landon","family":"Westfall","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Baker","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ref_1","unstructured":"CDC (2022, October 07). Scientific Brief: SARS-CoV-2 Transmission, Available online: https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/science\/science-briefs\/sars-cov-2-transmission.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","article-title":"2021. SARS-CoV-2 variants, spike mutations and immune escape","volume":"19","author":"Harvey","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"198563","DOI":"10.1016\/j.virusres.2021.198563","article-title":"Comparison of SARS-CoV-2 variant lethality in human angiotensin-converting enzyme 2 transgenic mice","volume":"305","author":"Lee","year":"2021","journal-title":"Virus Res."},{"key":"ref_4","first-page":"e13525","article-title":"SARS-CoV-2 viral spike G614 mutation exhibits higher case fatality rate","volume":"74","author":"Cardozo","year":"2020","journal-title":"Int. J. Clin. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.cell.2020.06.043","article-title":"Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus","volume":"182","author":"Korber","year":"2020","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1056\/NEJMc2100362","article-title":"New SARS-CoV-2 Variants\u2014Clinical, Public Health, and Vaccine Implications","volume":"384","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cherian, S., Potdar, V., Jadhav, S., Yadav, P., Gupta, N., Das, M., Rakshit, P., Singh, S., Abraham, P., and Obrenovich, E. (2021). SARS-CoV-2 Spike Mutations, L452R, T478K, E484Q and P681R, in the Second Wave of COVID-19 in Maharashtra, India. Microorganisms, 9.","DOI":"10.3390\/microorganisms9071542"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4220","DOI":"10.1016\/j.cell.2021.06.020","article-title":"Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum","volume":"184","author":"Liu","year":"2021","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Davis, C., Logan, N., Tyson, G., Orton, R., Harvey, W.T., Perkins, J.S., Mollett, G., Blacow, R.M., Peacock, T.P., and Barclay, W.S. (2021). Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1010022"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1016\/j.cell.2022.06.005","article-title":"Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum","volume":"185","author":"Tuekprakhon","year":"2022","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/s41592-022-01447-w","article-title":"Animal models in SARS-CoV-2 research","volume":"19","author":"Chu","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16587","DOI":"10.1073\/pnas.2009799117","article-title":"Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development","volume":"117","author":"Imai","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41586-022-04441-6","article-title":"SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters","volume":"603","author":"Halfmann","year":"2022","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6122","DOI":"10.1038\/s41467-020-19891-7","article-title":"Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice","volume":"11","author":"Oladunni","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1038\/s41590-020-0778-2","article-title":"SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function","volume":"21","author":"Winkler","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e142032","DOI":"10.1172\/jci.insight.142032","article-title":"Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease","volume":"5","author":"Golden","year":"2020","journal-title":"JCI Insight"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cell.2020.05.027","article-title":"Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2","volume":"182","author":"Liu","year":"2020","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41586-020-2943-z","article-title":"COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice","volume":"589","author":"Zheng","year":"2021","journal-title":"Nature"},{"key":"ref_19","unstructured":"Diamond, M., Halfmann, P., Maemura, T., Iwatsuki-Horimoto, K., Iida, S., Kiso, M., Scheaffer, S., Darling, T., Joshi, A., and Loeber, S. (Biol. Sci., 2021). The SARS-CoV-2 B.1.1.529 Omicron virus causes attenuated infection and disease in mice and hamsters, Biol. Sci., preprint."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1177\/03009858211057197","article-title":"Hamster models of COVID-19 pneumonia reviewed: How human can they be?","volume":"59","author":"Gruber","year":"2022","journal-title":"Vet. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1093\/infdis\/jiab361","article-title":"Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model","volume":"224","author":"Abdelnabi","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1128\/JVI.79.1.503-511.2005","article-title":"Severe Acute Respiratory Syndrome Coronavirus Infection of Golden Syrian Hamsters","volume":"79","author":"Roberts","year":"2005","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41586-020-2342-5","article-title":"Pathogenesis and transmission of SARS-CoV-2 in golden hamsters","volume":"583","author":"Sia","year":"2020","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.cell.2020.09.038","article-title":"Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity","volume":"183","author":"Ramirez","year":"2020","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"108728","DOI":"10.1016\/j.celrep.2021.108728","article-title":"Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients","volume":"34","author":"Tan","year":"2021","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100354","DOI":"10.1016\/j.xcrm.2021.100354","article-title":"Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells","volume":"2","author":"Cohen","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_27","first-page":"e2118312119","article-title":"Vaccine-induced systemic and mucosal T cell immunity to SARS-CoV-2 viral variants","volume":"119","author":"Lee","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1038\/s41590-020-0782-6","article-title":"Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19","volume":"21","author":"Peng","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.immuni.2019.04.011","article-title":"T follicular helper cell biology: A decade of discovery and diseases","volume":"50","author":"Crotty","year":"2019","journal-title":"Immunity"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1002\/jmv.27588","article-title":"Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines","volume":"94","author":"Araf","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"eabf4063","DOI":"10.1126\/science.abf4063","article-title":"Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection","volume":"371","author":"Dan","year":"2021","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100355","DOI":"10.1016\/j.xcrm.2021.100355","article-title":"Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals","volume":"2","author":"Tarke","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"eabj9853","DOI":"10.1126\/science.abj9853","article-title":"Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells","volume":"374","author":"Mateus","year":"2021","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nri.2015.10","article-title":"The multifaceted role of CD4+ T cells in CD8+ T cell memory","volume":"16","author":"Laidlaw","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1016\/j.cell.2020.05.015","article-title":"Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals","volume":"181","author":"Grifoni","year":"2020","journal-title":"Cell"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/11\/2584\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:22:58Z","timestamp":1760145778000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/11\/2584"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,21]]},"references-count":35,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["v14112584"],"URL":"https:\/\/doi.org\/10.3390\/v14112584","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2022,11,21]]}}}