{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T12:50:14Z","timestamp":1763988614065,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"Defense Threat Reduction Agency (DTRA) of the US Department of Defense","doi-asserted-by":"publisher","award":["HDTRA121C0005"],"award-info":[{"award-number":["HDTRA121C0005"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily causes mild to moderate respiratory illness in humans, but infection can also lead to long-term complications, including chronic fatigue, respiratory and cardiac issues, or even death. In November 2021, the emergence of the highly transmissible Omicron variant marked a significant shift in the pandemic, with its subvariants rapidly spreading and continuing to evolve worldwide. The continuing introduction of Omicron subvariants underscores the need for the development of up-to-date vaccines, as well as for appropriate animal models in which they can be evaluated. Among these subvariants, XBB.1.5 stands out for its ability to evade the immune response from previous infection or vaccination. The objective of this study was to determine the disease course in African green monkeys (AGMs) following intranasal exposure to the XBB.1.5 subvariant. In four intranasally exposed AGMs, histopathological findings in the lungs consistent with SARS-CoV-2 infection included lymphohistiocytic and neutrophilic bronchiolitis with variable numbers of syncytial cells, to terminal bronchiole-centric, bronchointerstitial pneumonia with alveolar type II (AT2) pneumocyte hyperplasia, with evidence of acute alveolar injury, including alveolar septal necrosis and hyaline membrane formation. The two males showed more severe pneumonia compared to the two females. SARS-CoV-2 RNA was detected in the lungs or tracheobronchial lymph nodes in the males but not in the females, which correlated with higher cumulative lung pathology scores in the males. In the females, SARS-CoV-2 RNA was limited to the colon and nasal turbinates. Our results indicate that AGMs exhibit a disease course similar to most humans when exposed intranasally, making them a suitable model for studying mild to moderate SARS-CoV-2 infection. Therefore, further work is warranted to determine if this model could have utility for the evaluation of vaccine and therapeutic candidates against contemporary SARS-CoV-2 variants.<\/jats:p>","DOI":"10.3390\/v17101373","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T10:37:14Z","timestamp":1760438234000},"page":"1373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["An Intranasal Challenge Model in African Green Monkeys (Chlorocebus aethiops) for Mild-to-Moderate COVID-19 Disease Caused by Subvariant XBB.1.5"],"prefix":"10.3390","volume":"17","author":[{"given":"Nadia","family":"Storm","sequence":"first","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Virology, Immunology and Microbiology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4280-3560","authenticated-orcid":false,"given":"Ming","family":"Lo","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Pathology and Laboratory Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3873-9188","authenticated-orcid":false,"given":"Nicholas","family":"Crossland","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Virology, Immunology and Microbiology, Boston University Chobanian and Avedisian School 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Mazur","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6204-4468","authenticated-orcid":false,"given":"Colleen","family":"Thurman","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlene","family":"Espinoza","sequence":"additional","affiliation":[{"name":"International AIDS Vaccine Initiative, New York, NY 10004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gavin","family":"Morrow","sequence":"additional","affiliation":[{"name":"International AIDS Vaccine 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Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1001\/jama.2020.5394","article-title":"Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy","volume":"323","author":"Grasselli","year":"2020","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A novel coronavirus from patients with pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_4","unstructured":"(2024, September 13). World Health Organization COVID-19 Dashboard. Available online: https:\/\/data.who.int\/dashboards\/covid19\/cases."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4958","DOI":"10.1038\/s41467-022-32665-7","article-title":"Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape","volume":"13","author":"Zhao","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.cell.2022.12.018","article-title":"Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants","volume":"186","author":"Wang","year":"2023","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1038\/s41467-024-46490-7","article-title":"Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86\/JN.1 lineages combining increased fitness and antibody evasion","volume":"15","author":"Planas","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hartman, A.L., Nambulli, S., McMillen, C.M., White, A.G., Tilston-Lunel, N.L., Albe, J.R., Cottle, E., Dunn, M.D., Frye, L.J., and Gilliland, T.H. (2020). SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET\/CT imaging and shedding of infectious virus from both respiratory and gastrointestinal tracts. PLoS Pathog., 16.","DOI":"10.1101\/2020.06.20.137687"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41590-020-00835-8","article-title":"Establishment of an African green monkey model for COVID-19 and protection against re-infection","volume":"22","author":"Woolsey","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lim, H., Baek, A., Kim, J., Kim, M.S., Liu, J., Nam, K.Y., Yoon, J., and No, K.T. (2020). Hot spot profiles of SARS-CoV-2 and human ACE2 receptor protein-protein interaction obtained by density functional tight binding fragment molecular orbital method. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-73820-8"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Coleman, C., Doyle-Meyers, L.A., Russell-Lodrigue, K.E., Golden, N., Threeton, B., Song, K., Pierre, G., Baribault, C., Bohm, R.P., and Maness, N.J. (2021). Similarities and differences in the acute-phase response to SARS-CoV-2 in Rhesus macaques and African green monkeys. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.754642"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ajpath.2020.10.016","article-title":"Acute respiratory distress in aged, SARS-CoV-2-infected African green monkeys but not rhesus macaques","volume":"191","author":"Blair","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_13","unstructured":"National Research Council (2021). Guide for the Care and Use of Laboratory Animals, The National Academies Press. [8th ed.]."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Honko, A.N., Storm, N., Bean, D.J., Henao Vasquez, J., Downs, S.N., and Griffiths, A. (2020). Rapid quantification and neutralization assays for novel coronavirus SARS-CoV-2 using Avicel RC-591 semi-solid overlay. Preprints, 2020050264.","DOI":"10.20944\/preprints202005.0264.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/s41586-020-2196-x","article-title":"Virological assessment of hospitalized patients with COVID-2019","volume":"581","author":"Corman","year":"2020","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s12985-020-01396-w","article-title":"Intranasal exposure of African green monkeys to SARS-CoV-2 results in acute phase pneumonia with shedding and lung injury still present in the early convalescence phase","volume":"17","author":"Cross","year":"2020","journal-title":"Virol. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1600-0684.2010.00422.x","article-title":"Clinical chemistry and hematology values in a Caribbean population of African green monkeys","volume":"39","author":"Liddie","year":"2010","journal-title":"J. Med. Primatol."},{"key":"ref_18","first-page":"E131","article-title":"Hematologic parameters in patients with COVID-19 infection","volume":"95","author":"Fan","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41590-021-01091-0","article-title":"Innate immunity: The first line of defense against SARS-CoV-2","volume":"23","author":"Diamond","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"105500","DOI":"10.1016\/j.jcv.2023.105500","article-title":"Severity outcomes associated with SARS-CoV-2 XBB variants, an observational analysis","volume":"165","author":"Klein","year":"2023","journal-title":"J. Clin. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Maison, D.P., Deng, Y., and Gerschenson, M. (2023). SARS-CoV-2 infection and the host immune response. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1195871"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e02370-20","DOI":"10.1128\/JVI.02370-20","article-title":"Comparison of subgenomic and total RNA in SARS-CoV-2-challenged rhesus macaques","volume":"95","author":"Dagotto","year":"2021","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1056\/NEJMoa2015432","article-title":"Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19","volume":"383","author":"Ackermann","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1161\/CIRCRESAHA.122.321636","article-title":"Pneumonia-induced inflammation, resolution and cardiovascular disease: Causes, consequences and clinical opportunities","volume":"132","author":"Stotts","year":"2023","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cytogfr.2020.04.002","article-title":"Cytokine storm intervention in the early stages of COVID-19 pneumonia","volume":"53","author":"Sun","year":"2020","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ijid.2022.12.004","article-title":"Identifying age- and sex-specific COVID-19 mortality trends over time in six countries","volume":"128","author":"Torres","year":"2023","journal-title":"Int. J. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Castellan, M., Zamperin, G., Franzoni, G., Foiani, G., Zorzan, M., Drzewniokov\u00e1, P., Mancin, M., Brian, I., Bortolami, A., and Pagliari, M. (2023). Host response of Syrian hamster to SARS-CoV-2 infection including differences with humans and between sexes. Viruses, 15.","DOI":"10.3390\/v15020428"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/10\/1373\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T10:38:20Z","timestamp":1760438300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/10\/1373"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":29,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["v17101373"],"URL":"https:\/\/doi.org\/10.3390\/v17101373","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]}}}