Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian Hamster Model

DOI record: { "DOI": "10.1038/s41429-023-00623-0", "ISSN": [ "0021-8820", "1881-1469" ], "URL": "http://dx.doi.org/10.1038/s41429-023-00623-0", "abstract": "<jats:title>Abstract</jats:title><jats:p>COVID-19, caused by SARS-CoV-2 infection, is currently among the most important public health concerns worldwide. Although several effective vaccines have been developed, there is an urgent clinical need for effective pharmaceutical treatments for treatment of COVID-19. Ivermectin, a chemical derivative of avermectin produced by <jats:italic>Streptomyces avermitilis</jats:italic>, is a macrocyclic lactone with antiparasitic activity. Recent studies have shown that ivermectin inhibits SARS-CoV-2 replication in vitro. In the present study, we investigated the in vivo effects of ivermectin in a hamster model of SARS-CoV-2 infection. The results of the present study demonstrate oral administration of ivermectin prior to SARS-CoV-2 infection in hamsters was associated with decreased weight loss and pulmonary inflammation. In addition, the administration of ivermectin reduced pulmonary viral titers and mRNA expression level of pro-inflammatory cytokines associated with severe COVID-19 disease. The administration of ivermectin rapidly induced the production of virus-specific neutralizing antibodies in the late stage of viral infection. Zinc concentrations leading to immune quiescence were also significantly higher in the lungs of ivermectin-treated hamsters compared to controls. These results indicate that ivermectin may have efficacy in reducing the development and severity of COVID-19 by affecting host immunity in a hamster model of SARS-CoV-2 infection.</jats:p>", "alternative-id": [ "623" ], "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "5 January 2023" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Revised", "name": "revised", "order": 2, "value": "22 March 2023" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 3, "value": "5 April 2023" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 4, "value": "25 April 2023" }, { "group": { "label": "Compliance with ethical standards", "name": "EthicsHeading" }, "name": "Ethics", "order": 1 }, { "group": { "label": "Conflict of interest", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "The authors declare no competing interests." } ], "author": [ { "ORCID": "http://orcid.org/0000-0002-3680-7231", "affiliation": [], "authenticated-orcid": false, "family": "Uematsu", "given": "Takayuki", "sequence": "first" }, { "affiliation": [], "family": "Takano", "given": "Tomomi", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-0099-3340", "affiliation": [], "authenticated-orcid": false, "family": "Matsui", "given": "Hidehito", "sequence": "additional" }, { "affiliation": [], "family": "Kobayashi", "given": "Noritada", "sequence": "additional" }, { "affiliation": [], "family": "Ōmura", "given": "Satoshi", "sequence": "additional" }, { "affiliation": [], "family": "Hanaki", "given": "Hideaki", "sequence": "additional" } ], "container-title": "The Journal of Antibiotics", "container-title-short": "J Antibiot", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2023, 4, 25 ] ], "date-time": "2023-04-25T10:03:30Z", "timestamp": 1682417010000 }, "deposited": { "date-parts": [ [ 2023, 4, 25 ] ], "date-time": "2023-04-25T10:07:43Z", "timestamp": 1682417263000 }, "indexed": { "date-parts": [ [ 2023, 4, 26 ] ], "date-time": "2023-04-26T05:01:39Z", "timestamp": 1682485299130 }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2023, 4, 25 ] ] }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 4, 25 ] ], "date-time": "2023-04-25T00:00:00Z", "timestamp": 1682380800000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 4, 25 ] ], "date-time": "2023-04-25T00:00:00Z", "timestamp": 1682380800000 } } ], "link": [ { "URL": "https://www.nature.com/articles/s41429-023-00623-0.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41429-023-00623-0", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41429-023-00623-0.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1038", "published": { "date-parts": [ [ 2023, 4, 25 ] ] }, "published-online": { "date-parts": [ [ 2023, 4, 25 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1001/jama.2020.12839", "author": "WJ Wiersinga", "doi-asserted-by": "publisher", "first-page": "782", "journal-title": "JAMA", "key": "623_CR1", "unstructured": "Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020;324:782–93.", "volume": "324", "year": "2020" }, { "DOI": "10.1038/s41584-021-00608-z", "author": "M Ramos-Casals", "doi-asserted-by": "publisher", "first-page": "315", "journal-title": "Nat Rev Rheumatol", "key": "623_CR2", "unstructured": "Ramos-Casals M, Brito-Zerón P, Mariette X. Systemic and organ-specific immune-related manifestations of COVID-19. Nat Rev Rheumatol. 2021;17:315–32.", "volume": "17", "year": "2021" }, { "DOI": "10.1001/jamacardio.2020.3557", "author": "VO Puntmann", "doi-asserted-by": "publisher", "first-page": "1265", "journal-title": "JAMA Cardiol", "key": "623_CR3", "unstructured": "Puntmann VO, et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered from Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020;5:1265–73.", "volume": "5", "year": "2020" }, { "DOI": "10.1186/s12913-020-06001-y", "author": "E Ladds", "doi-asserted-by": "publisher", "journal-title": "BMC Health Serv Res", "key": "623_CR4", "unstructured": "Ladds E, et al. Persistent symptoms after Covid-19: qualitative study of 114 “long Covid” patients and draft quality principles for services. BMC Health Serv Res. 2020;20:1144.", "volume": "20", "year": "2020" }, { "DOI": "10.3389/fimmu.2020.585354", "author": "O Sharma", "doi-asserted-by": "publisher", "first-page": "585354", "journal-title": "Front Immunol", "key": "623_CR5", "unstructured": "Sharma O, Sultan AA, Ding H, Triggle CR. A Review of the Progress and Challenges of Developing a Vaccine for COVID-19. Front Immunol. 2020;11:585354.", "volume": "11", "year": "2020" }, { "DOI": "10.1016/j.ejphar.2020.173751", "author": "K Rawat", "doi-asserted-by": "publisher", "first-page": "173751", "journal-title": "Eur J Pharm", "key": "623_CR6", "unstructured": "Rawat K, Kumari P, Saha L. COVID-19 vaccine: A recent update in pipeline vaccines, their design and development strategies. Eur J Pharm. 2021;892:173751.", "volume": "892", "year": "2021" }, { "DOI": "10.1038/s41586-021-03412-7", "author": "DA Collier", "doi-asserted-by": "publisher", "first-page": "136", "journal-title": "Nature", "key": "623_CR7", "unstructured": "Collier DA, et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature. 2021;593:136–41.", "volume": "593", "year": "2021" }, { "DOI": "10.1136/bmj-2021-067873", "author": "A Israel", "doi-asserted-by": "publisher", "first-page": "e067873", "journal-title": "BMJ", "key": "623_CR8", "unstructured": "Israel A, et al. Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection: test negative design study. BMJ. 2021;375:e067873.", "volume": "375", "year": "2021" }, { "DOI": "10.1038/nrmicro1048", "author": "S Õmura", "doi-asserted-by": "publisher", "first-page": "984", "journal-title": "Nat Rev Microbiol", "key": "623_CR9", "unstructured": "Õmura S, Crump A. The life and times of ivermectin—A success story. Nat Rev Microbiol. 2004;2:984–9.", "volume": "2", "year": "2004" }, { "DOI": "10.2183/pjab.87.13", "author": "A Crump", "doi-asserted-by": "publisher", "first-page": "13", "journal-title": "Proc Jpn Acad Sers B Phys Biol Sci", "key": "623_CR10", "unstructured": "Crump A, Omura S. Ivermectin, ‘Wonder drug’ from Japan: The human use perspective. Proc Jpn Acad Sers B Phys Biol Sci. 2011;87:13–28.", "volume": "87", "year": "2011" }, { "DOI": "10.1016/j.antiviral.2020.104787", "author": "L Caly", "doi-asserted-by": "publisher", "first-page": "104787", "journal-title": "Antivir Res", "key": "623_CR11", "unstructured": "Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res. 2020;178:104787.", "volume": "178", "year": "2020" }, { "author": "M Popp", "first-page": "CD015017", "journal-title": "Cochrane Database Syst Rev", "key": "623_CR12", "unstructured": "Popp M, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev. 2022;6:CD015017.", "volume": "6", "year": "2022" }, { "DOI": "10.1038/s41586-020-2342-5", "author": "SF Sia", "doi-asserted-by": "publisher", "first-page": "834", "journal-title": "Nature", "key": "623_CR13", "unstructured": "Sia SF, et al. Pathogenesis and transmission of SARS-CoV-2 in golden hamsters. Nature. 2020;583:834–8.", "volume": "583", "year": "2020" }, { "DOI": "10.1073/pnas.2009799117", "author": "M Imai", "doi-asserted-by": "publisher", "first-page": "16587", "journal-title": "Proc Nat Acad Sci USA", "key": "623_CR14", "unstructured": "Imai M, et al. Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. Proc Nat Acad Sci USA. 2020;117:16587–95.", "volume": "117", "year": "2020" }, { "DOI": "10.1093/cid/ciaa644", "author": "JF-W Chan", "doi-asserted-by": "publisher", "first-page": "2428", "journal-title": "Clin Infect Dis", "key": "623_CR15", "unstructured": "Chan JF-W, et al. Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility. Clin Infect Dis. 2020;71:2428–46.", "volume": "71", "year": "2020" }, { "DOI": "10.1016/j.celrep.2021.109218", "author": "T Ebisudani", "doi-asserted-by": "publisher", "first-page": "109218", "journal-title": "Cell Rep", "key": "623_CR16", "unstructured": "Ebisudani T, et al. Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening. Cell Rep. 2021;35:109218.", "volume": "35", "year": "2021" }, { "DOI": "10.1073/pnas.2002589117", "author": "S Matsuyama", "doi-asserted-by": "publisher", "first-page": "7001", "journal-title": "Proc Nat Acad Sci USA", "key": "623_CR17", "unstructured": "Matsuyama S, et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Nat Acad Sci USA. 2020;117:7001–3.", "volume": "117", "year": "2020" }, { "DOI": "10.1016/j.cell.2021.02.029", "author": "JL Schultze", "doi-asserted-by": "publisher", "first-page": "1671", "journal-title": "Cell", "key": "623_CR18", "unstructured": "Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell. 2021;184:1671–92.", "volume": "184", "year": "2021" }, { "DOI": "10.1038/s41579-021-00542-7", "author": "T Flerlage", "doi-asserted-by": "publisher", "first-page": "425", "journal-title": "Nat Rev Microbiol", "key": "623_CR19", "unstructured": "Flerlage T, Boyd DF, Meliopoulos V, Thomas PG, Schultz-Cherry S. Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract. Nat Rev Microbiol. 2021;19:425–41.", "volume": "19", "year": "2021" }, { "DOI": "10.1073/pnas.1517188113", "author": "M Nishio", "doi-asserted-by": "publisher", "first-page": "E71", "journal-title": "Proc Natl Acad Sci USA", "key": "623_CR20", "unstructured": "Nishio M, et al. Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. Proc Natl Acad Sci USA. 2016;113:E71–80.", "volume": "113", "year": "2016" }, { "DOI": "10.18632/oncotarget.22587", "author": "S Nambara", "doi-asserted-by": "publisher", "first-page": "107666", "journal-title": "Oncotarget", "key": "623_CR21", "unstructured": "Nambara S, et al. Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer. Oncotarget. 2017;8:107666–77.", "volume": "8", "year": "2017" }, { "DOI": "10.1042/BJ20120150", "author": "KM Wagstaff", "doi-asserted-by": "publisher", "first-page": "851", "journal-title": "Biochem J", "key": "623_CR22", "unstructured": "Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443:851–6.", "volume": "443", "year": "2012" }, { "DOI": "10.1371/journal.pntd.0006934", "author": "TL Xu", "doi-asserted-by": "publisher", "first-page": "e0006934", "journal-title": "PLoS Negl Trop Dis", "key": "623_CR23", "unstructured": "Xu TL, et al. Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus. PLoS Negl Trop Dis. 2018;12:e0006934.", "volume": "12", "year": "2018" }, { "DOI": "10.1016/j.antiviral.2020.104760", "author": "SNY Yang", "doi-asserted-by": "publisher", "first-page": "104760", "journal-title": "Antivir Res", "key": "623_CR24", "unstructured": "Yang SNY, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antivir Res. 2020;177:104760.", "volume": "177", "year": "2020" }, { "DOI": "10.1002/jmv.26610", "author": "CW Stratton", "doi-asserted-by": "publisher", "first-page": "1320", "journal-title": "J Med Virol", "key": "623_CR25", "unstructured": "Stratton CW, Tang YW, Lu H. Pathogenesis-directed therapy of 2019 novel coronavirus disease. J Med Virol. 2021;93:1320–42.", "volume": "93", "year": "2021" }, { "DOI": "10.1080/22221751.2020.1823890", "author": "P Wang", "doi-asserted-by": "publisher", "first-page": "2091", "journal-title": "Emerg Microbes Infect", "key": "623_CR26", "unstructured": "Wang P, et al. SARS-CoV-2 neutralizing antibody responses are more robust in patients with severe disease. Emerg Microbes Infect. 2020;9:2091–3.", "volume": "9", "year": "2020" }, { "DOI": "10.15252/emmm.202114122", "author": "GD de Melo", "doi-asserted-by": "publisher", "first-page": "e14122", "journal-title": "EMBO Mol Med", "key": "623_CR27", "unstructured": "de Melo GD, et al. Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin. EMBO Mol Med. 2021;13:e14122.", "volume": "13", "year": "2021" }, { "DOI": "10.1038/s41598-021-86679-0", "author": "AP Arévalo", "doi-asserted-by": "publisher", "journal-title": "Sci Rep", "key": "623_CR28", "unstructured": "Arévalo AP, et al. Ivermectin reduces in vivo coronavirus infection in a mouse experimental model. Sci Rep. 2021;11:7132.", "volume": "11", "year": "2021" }, { "DOI": "10.1371/journal.ppat.1006955", "author": "H Namkoong", "doi-asserted-by": "publisher", "first-page": "e1006955", "journal-title": "PLoS Pathog", "key": "623_CR29", "unstructured": "Namkoong H, et al. Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia. PLoS Pathog. 2018;14:e1006955.", "volume": "14", "year": "2018" }, { "DOI": "10.1016/j.ejphar.2021.174191", "author": "MR Khezri", "doi-asserted-by": "publisher", "first-page": "174191", "journal-title": "Eur J Pharm", "key": "623_CR30", "unstructured": "Khezri MR, Zolbanin NM, Ghasemnejad-berenji M, Jafari R. Azithromycin: Immunomodulatory and antiviral properties for SARS-CoV-2 infection. Eur J Pharm. 2021;905:174191.", "volume": "905", "year": "2021" }, { "DOI": "10.3389/fimmu.2021.574425", "author": "VJ Venditto", "doi-asserted-by": "publisher", "first-page": "574425", "journal-title": "Front Immunol", "key": "623_CR31", "unstructured": "Venditto VJ, et al. Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19. Front Immunol. 2021;12:574425.", "volume": "12", "year": "2021" }, { "DOI": "10.3390/microorganisms10122438", "author": "JM Blondeau", "doi-asserted-by": "publisher", "first-page": "2438", "journal-title": "Microorganisms", "key": "623_CR32", "unstructured": "Blondeau JM. Immunomodulatory Effects of Macrolides Considering Evidence from Human and Veterinary Medicine. Microorganisms. 2022;10:2438.", "volume": "10", "year": "2022" }, { "DOI": "10.1007/s43440-020-00195-y", "author": "H Kaur", "doi-asserted-by": "publisher", "first-page": "736", "journal-title": "Pharm Rep", "key": "623_CR33", "unstructured": "Kaur H, et al. Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes. Pharm Rep. 2021;73:736–49.", "volume": "73", "year": "2021" }, { "DOI": "10.1016/S0065-2776(08)00003-5", "author": "T Hirano", "doi-asserted-by": "publisher", "first-page": "149", "journal-title": "Adv Immunol", "key": "623_CR34", "unstructured": "Hirano T, et al. Roles of Zinc and Zinc Signaling in Immunity: Zinc as an Intracellular Signaling Molecule. Adv Immunol. 2008;97:149–76.", "volume": "97", "year": "2008" }, { "DOI": "10.1038/ni.f.220", "author": "M Vig", "doi-asserted-by": "publisher", "first-page": "21", "journal-title": "Nat Immunol", "key": "623_CR35", "unstructured": "Vig M, Kinet JP. Calcium signaling in immune cells. Nat Immunol. 2009;10:21–7.", "volume": "10", "year": "2009" }, { "DOI": "10.1371/journal.ppat.1001176", "author": "AJW te Velthuis", "doi-asserted-by": "publisher", "first-page": "e1001176", "journal-title": "PLoS Pathog", "key": "623_CR36", "unstructured": "te Velthuis AJW, et al. Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture. PLoS Pathog. 2010;6:e1001176.", "volume": "6", "year": "2010" }, { "DOI": "10.1016/j.mehy.2020.109848", "author": "A Kumar", "doi-asserted-by": "publisher", "first-page": "109848", "journal-title": "Med Hypotheses", "key": "623_CR37", "unstructured": "Kumar A, Kubota Y, Chernov M, Kasuya H. Potential role of zinc supplementation in prophylaxis and treatment of COVID-19. Med Hypotheses. 2020;144:109848.", "volume": "144", "year": "2020" }, { "DOI": "10.1038/ni1373", "author": "H Kitamura", "doi-asserted-by": "publisher", "first-page": "971", "journal-title": "Nat Immunol", "key": "623_CR38", "unstructured": "Kitamura H, et al. Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol. 2006;7:971–7.", "volume": "7", "year": "2006" }, { "DOI": "10.1038/s41586-022-05594-0", "author": "T Brevini", "doi-asserted-by": "publisher", "first-page": "134", "journal-title": "Nature", "key": "623_CR39", "unstructured": "Brevini T, et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature. 2023;615:134–42.", "volume": "615", "year": "2023" }, { "DOI": "10.1038/ncomms2924", "author": "L Jin", "doi-asserted-by": "publisher", "journal-title": "Nat Commun", "key": "623_CR40", "unstructured": "Jin L, et al. The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nat Commun. 2013;4:1937.", "volume": "4", "year": "2013" } ], "reference-count": 40, "references-count": 40, "relation": {}, "resource": { "primary": { "URL": "https://www.nature.com/articles/s41429-023-00623-0" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Drug Discovery", "Pharmacology" ], "subtitle": [], "title": "Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian Hamster Model", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1007/springer_crossmark_policy" }